Novel heterocyclic acrylamides and their use as pharmaceuticals

ABSTRACT

The invention relates to novel heterocyclic acrylamide compounds (I), to the preparation of the compounds and intermediates used therein, to the use of the compounds as antibacterial medicaments and pharmaceutical compositions containing the compounds.

This application is a divisional of U.S. application Ser. No. 14/463,994(allowed), filed Aug. 20, 2014 (published as US 2014-0357617 A1), whichis a divisional of U.S. application Ser. No. 13/510,564 (now U.S. Pat.No. 8,846,711), filed Jul. 12, 2012 (published as US 2012-0277207 A1),which is a U.S. national phase of International Application No.PCT/EP2010/067647 filed 17 Nov. 2010 which designated the U.S. andclaims priority to U.S. Provisional Application No. 61/262,309 filed 18Nov. 2009, the entire contents of each of which are hereby incorporatedby reference.

FIELD OF THE INVENTION

The invention relates to novel heterocyclic acrylamide compounds, to thepreparation of the compounds and intermediates used therein, to the useof the compounds as antibacterial medicaments and pharmaceuticalcompositions containing the compounds.

BACKGROUND OF THE INVENTION

The invention particularly relates to new compounds capable ofinhibiting bacterial and/or parasite fatty acid biosynthesis and theiruse as antibacterial and/or antiparasitic agents.

The emergence of antibiotic-resistant pathogens has become a seriousworldwide healthcare problem. Indeed, some infections are now caused bymulti-drug resistant organisms that are no longer responsive tocurrently available treatments. There is therefore an immediate need fornew antibacterial/antiparasitic agents with a novel mode of action.

The bacterial fatty acid biosynthesis (FASII system) has recentlygenerated a lot of interest for the development of novelantibacterial/antiparasitic agents (Rock et al. J. Biol. Chem. 2006,281, 17541; Wright and Reynolds Curr. Opin. Microbiol. 2007, 10, 447).The organization of components in the bacterial fatty acid biosynthesispathway based on discrete enzymes is fundamentally different from themultifunctional FASI system found in mammals, therefore allowing goodprospects of selective inhibition. The overall high degree ofconservation in many enzymes of the bacterial FASII system should alsoallow the development of broader-spectrum antibacterial/antiparasiticagents.

Among all the monofunctional enzymes of the bacterial FASII system, FabIrepresents the enoyl-ACP reductase responsible for the last step of thefatty acid biosynthetic elongation cycle. Using the cofactor NAD(P)H asa hydride source, FabI reduces the double bond in the trans-2-enoyl-ACPintermediate to the corresponding acyl-ACP product. This enzyme has beenshown to constitute an essential target in major pathogens such as E.coli (Heath et al. J. Biol. Chem. 1995, 270, 26538; Bergler et al. Eur.J. Biochem. 1996, 242, 689) and S. aureus (Heath et al. J. Biol. Chem.2000, 275, 4654). However, other isoforms have been isolated such asFabK from S. pneumoniae (Heath et al. Nature 2000, 406, 145) and FabLfrom B. subtilis (Heath et al. J. Biol. Chem. 2000, 275, 40128).Although FabK is structurally and mechanistically unrelated to FabI(Marrakchi et al. Biochem J. 2003, 370, 1055), the similarity of FabIwith FabL (B. subtilis), InhA (M. tuberculosis) and PfENR (P.falciparum) still offers opportunities of interesting activity spectra(Heath et al. Prog. Lipid Res. 2001, 40, 467).

Several FabI inhibitors have already been reported in the literature(Tonge et al. Acc. Chem. Res. 2008, 41, 11). Some of them such asdiazaborines (Baldock et al. Science 1996, 274, 2107) and isoniazid inits activated form (Tonge et al. Proc. Natl. Acad. Sci. U.S.A. 2003,100, 13881) act by covalently modifying the cofactor NAD+. However somedrawbacks are associated with these products. Diazaborines are only usedexperimentally because of their inherent toxicity (Baldock et al.Biochem. Pharmacol. 1998, 55, 1541) while isoniazid is a prodrugrestricted to the treatment of susceptible tuberculosis. The fact thatisoniazid requires activation by hydrogen-peroxyde inducible enzymes(Schultz et al. J. Am. Chem. Soc. 1995, 117, 5009) enhances thepossibilities of resistance by lack of activation or increaseddetoxification (Rosner et al. Antimicrob. Agents Chemother. 1993, 37,2251 and ibid 1994, 38, 1829).

Other inhibitors act by interacting noncovalently with theenzyme-cofactor complex. For instance Triclosan, a widely used consumergoods preservative with broad spectrum antimicrobial activity, has beenfound to be a reversible, tight-binding inhibitor of E. coli FabI (Wardet al. Biochemistry 1999, 38, 12514). Intravenous toxicology studies onthis compound indicated a LD₅₀ on rats of 29 mg/kg clearly ruling outintravenous injection (Lyman et al. Ind. Med. Surg. 1969, 38, 42).Derivatives based on the 2-hydroxydiphenyl ether core of Triclosan havebeen reported (Tonge et al. J. Med. Chem. 2004, 47, 509, ACS Chem Biol.2006, 1, 43 and Bioorg. Med. Chem. Lett. 2008, 18, 3029; Surolia et al.Bioorg. Med. Chem. 2006, 14, 8086 and ibid 2008, 16, 5536; Freundlich etal. J. Biol. Chem. 2007, 282, 25436) as well as other inhibitors basedon various classes of high throughput screening derived templates(Seefeld et al. Bioorg. Med. Chem. Lett. 2001, 11, 2241 and J. Med.Chem. 2003, 46, 1627; Heerding et al. Bioorg. Med. Chem. Lett. 2001, 11,2061; Miller et al. J. Med. Chem. 2002, 45, 3246; Payne et al.Antimicrob. Agents Chemother. 2002, 46, 3118; Sacchettini et al. J.Biol. Chem. 2003, 278, 20851; Moir et al. Antimicrob. Agents Chemother.2004, 48, 1541; Montellano et al. J. Med. Chem. 2006, 49, 6308; Kwak etal. Int. J. Antimicro. Ag. 2007, 30, 446; Lee et al. Antimicrob. AgentsChemother. 2007, 51, 2591; Kitagawa et al. J. Med. Chem. 2007, 50, 4710,Bioorg. Med. Chem. 2007, 15, 1106 and Bioorg. Med. Chem. Lett. 2007, 17,4982; Takahata et al. J. Antibiot. 2007, 60, 123; Kozikowski et al.Bioorg. Med. Chem. Lett. 2008, 18, 3565), nevertheless none of theseinhibitors have succeeded yet as a drug. Interestingly, some classes ofthese inhibitors display activity on both FabI and FabK: predominantlyFabK for the dual compounds based on phenylimidazole derivatives of4-pyridones (Kitagawa et al. J. Med. Chem. 2007, 50, 4710),predominantly FabI for the indole derivatives (Payne et al. Antimicrob.Agents Chemother. 2002, 46, 3118; Seefeld et al. J. Med. Chem. 2003, 46,1627). However, the moderate activity on the second enzyme might proveto be a drawback for such compounds as it may lead to an increase ofresistance mechanisms due to the added selection pressure (Tonge et al.Acc. Chem. Res. 2008, 41, 11).

Despite the attractiveness of FabI as an antibacterial/antiparasitictarget, it is still largely unexploited at this time since there are nodrugs on the market or within advanced clinical phases.

WO 2007/135562 (Mutabilis SA) describes a series of hydroxyphenylderivatives that display a selective spectrum of activity on speciescontaining FabI and related targets, in contrast to Triclosan. WO2008/098374, WO 2008/009122, WO 2007/067416, WO 2007/053131, WO03/088897 and WO 01/27103 (Affinium Pharmaceuticals Inc) all describe aseries of acrylamide derivatives which are claimed to be FabIinhibitors.

One of the purposes of the invention is to provide novel compoundsactive on FabI and related targets with improved pharmacological and/orphysico-chemical properties over existing compounds.

SUMMARY OF THE INVENTION

According to a first aspect of the invention, there is provided acompound of formula (I):

wherein:

-   -   W and X independently represent a bond or a —(CH₂)₁₋₄ group,        such that W and X together contain 1-5 carbon atoms;    -   R1 represents an H, F, CN, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,        (C₂-C₆) alkynyl, CO₂R_(d), COR_(d), CONR_(a)R_(b), OCOR_(d),        OR_(d), NR_(a)R_(b), ON═CR_(d)R_(e), NR_(c)COR_(d),        NR_(c)COOR_(d), OCONR_(a)R_(b), NR_(c)CONR_(a)R_(b),        NR_(c)SO₂R—S(O)_(n)R_(a), SO₂NR_(a)R_(b), —C(R_(a))═N—O—R_(f),        Y—Ar or a Z-Het group, wherein Ar represents phenyl or naphthyl,        Het represents a 4-10 membered monocyclic or bicyclic saturated        or unsaturated heterocycle containing 1-5 heteroatoms selected        from N, O and S and Y and Z independently represent a bond or a        linker selected from O, S, CO, (C₁-C₆) alkylene, —O—(C₁-C₆)        alkylene, —CO—(C₁-C₆) alkylene or —ON═CR_(d)—(C₁-C₆) alkylene,        wherein said R1 group may be optionally substituted by one or        more R4 groups;    -   R2 represents an H, F, CN, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,        (C₂-C₆) alkynyl, CO₂R_(d), COR_(d), CONR_(a)R_(b), OCOR_(d),        OR_(d), NR_(a)R_(b), ON═CR_(d)R_(e), NR_(c)COR_(d),        NR_(c)COOR_(d), OCONR_(a)R_(b), NR_(c)CONR_(a)R_(b),        NR_(c)SO₂R_(a), S(O)_(n)R_(a) or SO₂NR_(a)R_(b) group;    -   R_(a), R_(b) and R_(c) independently represent H, (C₁-C₆) alkyl,        (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, or an NR_(a)R_(b) group may        optionally form a 3- to 7-membered nitrogen containing saturated        heterocycle optionally containing 1 to 3 additional heteroatoms        selected from N, O or S wherein said heterocycle may be        optionally substituted by one or more (C₁-C₆) alkyl groups;    -   R_(d) and R_(e) independently represent H, (C₁-C₆) alkyl,        (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, halo(C₁-C₆) alkyl, halo(C₁-C₆)        alkyl-O—(C₁-C₆) alkyl- or (C₁-C₆) alkyl-O—(C₁-C₆) alkyl-;    -   R_(f) represents (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆)        alkynyl, halo(C₁-C₆) alkyl or —(C₁-C₆) alkyl-Ar, wherein Ar        represents phenyl or naphthyl;    -   R4 represents halogen, CN, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,        (C₂-C₆) alkynyl, CO₂R_(d), COR_(d), CONR_(a)R_(b), OCOR_(d),        OR_(d), NR_(a)R_(b), ON═CR_(d)R_(e), NR_(c)COR_(d),        NR_(c)COOR_(d), OCONR_(a)R_(b), NR_(c)CONR_(a)R_(b),        NR_(c)SO₂R_(a), S(O)_(n)R_(a), or SO₂NR_(a)R_(b);    -   n represents an integer selected from 0 to 2;    -   R3 is a pyridyl ring optionally fused to a 5, 6 or 7 membered        aromatic, partially aromatic or saturated heterocycle containing        1-3 heteroatoms selected from N, O and S, wherein said R3 group        may be optionally substituted by one or more R5 groups;    -   R5 is selected from the group consisting of F, CO₂R_(d),        COR_(d), CONR_(a)R_(b), OR_(d), ═O, NR_(a)R_(b), NR_(c)COR_(d)        or (C₁-C₆) alkyl optionally substituted by F, CO₂R_(d),        CONR_(a)R_(b), OR_(d), NR_(a)R_(b), NR_(a)COR_(d) or Het        optionally substituted by one or more (C₁-C₆) alkyl groups, or        two R5 groups together with the atom to which they are attached        may together form a Het group optionally substituted by one or        more (C₁-C₆) alkyl groups;        or a pharmaceutically acceptable salt or solvate thereof.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 relates to the in vivo antibacterial activity of Example 12 at100 mg/kg; and

FIG. 2 relates to the in vivo antibacterial activity of Example 15 at 50mg/kg.

DETAILED DESCRIPTION OF THE INVENTION

According to one particular aspect of the invention which may bementioned, there is provided a compound of formula (I):

wherein:

-   -   W and X independently represent a bond or a —(CH₂)₁₋₄ group,        such that W and X together contain 1-5 carbon atoms;    -   R1 represents an H, F, CN, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,        (C₂-C₆) alkynyl, CO₂R_(d), COR_(d), CONR_(a)R_(b), OCOR_(d),        OR_(d), NR_(a)R_(b), ON═CR_(d)R_(e), NR_(c)COR_(d),        NR_(c)COOR_(d), OCONR_(a)R_(b), NR_(c)CONR_(a)R_(b),        NR_(c)SO₂R—S(O)_(n)R_(a), SO₂NR_(a)R_(b), Y—Ar or a Z-Het group,        wherein Ar represents phenyl or naphthyl, Het represents a 4-10        membered monocyclic or bicyclic saturated or unsaturated        heterocycle containing 1-5 heteroatoms selected from N, O and S        and Y and Z independently represent a bond or a linker selected        from O, CO, (C₁-C₆) alkylene, —O—(C₁-C₆) alkylene, —CO—(C₁-C₆)        alkylene or —ON═CR_(d)—(C₁-C₆) alkylene, wherein said R1 group        may be optionally substituted by one or more R4 groups;    -   R2 represents an H, F, CN, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,        (C₂-C₆) alkynyl, CO₂R_(d), COR_(d), CONR_(a)R_(b), OCOR_(d),        OR_(d), NR_(a)R_(b), ON═CR_(d)R_(e), NR_(c)COR_(d),        NR_(c)COOR_(d), OCONR_(a)R_(b), NR_(c)CONR_(a)R_(b),        NR_(c)SO₂R—S(O)_(n)R_(a) or SO₂NR_(a)R_(b) group;    -   R_(a), R_(b) and R_(c) independently represent H, (C₁-C₆) alkyl,        (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, or an NR_(a)R_(b) group may        optionally form a 3- to 7-membered nitrogen containing saturated        heterocycle optionally containing 1 to 3 additional heteroatoms        selected from N, O or S wherein said heterocycle may be        optionally substituted by one or more (C₁-C₆) alkyl groups;    -   R_(d) and R_(e) independently represent H, (C₁-C₆) alkyl,        (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, halo(C₁-C₆) alkyl, halo(C₁-C₆)        alkyl-O—(C₁-C₆) alkyl- or (C₁-C₆) alkyl-O—(C₁-C₆) alkyl-;    -   R4 represents halogen, CN, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,        (C₂-C₆) alkynyl, CO₂R_(d), COR_(d), CONR_(a)R_(b), OCOR_(d),        OR_(d), NR_(a)R_(b), ON═CR_(d)R_(e), NR_(c)COR_(d),        NR_(c)COOR_(d), OCONR_(a)R_(b), NR_(c)CONR_(a)R_(b),        NR_(c)SO₂R_(a), S(O)_(n)R_(a), or SO₂NR_(a)R_(b);    -   n represents an integer selected from 0 to 2;    -   R3 is a pyridyl ring optionally fused to a 5, 6 or 7 membered        aromatic, partially aromatic or saturated heterocycle containing        1-3 heteroatoms selected from N, O and S, wherein said R3 group        may be optionally substituted by one or more R5 groups;    -   R5 is selected from the group consisting of F, CO₂R_(d),        COR_(d), CONR_(a)R_(b), OR_(d), ═O, NR_(a)R_(b), NR_(c)COR_(d)        or (C₁-C₆) alkyl optionally substituted by F, CO₂R_(d),        CONR_(a)R_(b), OR_(d), NR_(a)R_(b), NR_(a)COR_(d), or two R5        groups together with the atom to which they are attached may        together form a Het group optionally substituted by one or more        (C₁-C₆) alkyl groups;        or a pharmaceutically acceptable salt or solvate thereof.

The compounds of the invention may have good in vitro and/or in vivoactivity and display surprisingly improved pharmacological, physicaland/or chemical properties over previously described FabI inhibitors asconfirmed by data presented herein. For example, compounds of theinvention which have been tested display surprisingly less serum bindingthan previously described acrylamide derivatives. Furthermore, compoundsof the invention which have been tested appear to demonstrate parenteral(such as subcutaneous) and oral bioavailability. Certain compounds ofthe invention also appear to reduce the apparition of resistancemechanisms by being selective of FabI and related targets while avoidinghitting structurally unrelated targets such as FabK. In addition,compounds of the invention which have been tested appear to demonstrategreater solubility than previously described FabI inhibitors.

In the present context, the term “pharmaceutically acceptable salt” isintended to indicate salts which are not harmful to the patient. Suchsalts include pharmaceutically acceptable acid addition salts,pharmaceutically acceptable metal salts and pharmaceutically acceptableakaline addition salts. Acid addition salts include salts of inorganicacids as well as organic acids.

Representative examples of suitable inorganic acids includehydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitricacids and the like. Representative examples of suitable organic acidsinclude formic, acetic, trichloroacetic, trifluoroacetic, propionic,benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic,malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic,methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic,bismethylene salicylic, ethanedisulfonic, gluconic, citraconic,aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic,benzenesulfonic, p-toluenesulfonic acids and the like. Further examplesof pharmaceutically acceptable inorganic or organic acid addition saltsinclude the pharmaceutically acceptable salts listed in J. Pharm. Sci.1977, 66, 2, which is incorporated herein by reference. Examples ofmetal salts include lithium, sodium, potassium, magnesium salts and thelike. Examples of ammonium and alkylated ammonium salts includeammonium, methylammonium, dimethylammonium, trimethylammonium,ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium,tetramethylammonium salts and the like.

Representative examples of alkaline salts include, for example, sodium,potassium, lithium, calcium, magnesium or ammonium or organic bases suchas, for example, methylamine, ethylamine, propylamine, trimethylamine,diethylamine, triethylamine, N,N-dimethylethanolamine,tris(hydroxymethyl)aminomethane, ethanolamine, pyridine, piperidine,piperazine, picoline, dicyclohexylamine, morpholine, benzylamine,procaine, lysine, arginine, histidine, N-methylglucamine.

According to the invention, the compounds of formula (I) can be inracemic forms, as well as in the form of pure enantiomers or non racemic(scalemic) mixture of enantiomers, including when the compounds offormula (I) have more than one stereogenic centre. In case the compoundsof formula (I) have unsaturated carbon carbon double bonds, both the cis(Z) and trans (E) isomers and their mixtures belong to the invention.

References herein to “halogen” means a fluorine, chlorine, bromine oriodine atom.

References herein to “(C₁-C₆) alkyl” means any linear, branchedhydrocarbon groups having 1 to 6 carbon atoms, or cyclic hydrocarbongroups having 3 to 6 carbon atoms. Representative examples of such alkylgroups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl andt-butyl, n-pentyl, isopentyl, neopentyl, cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl.

References herein to “(C₂-C₆) alkenyl” means any linear, branchedhydrocarbon groups of 2 to 6 carbon atoms, or cyclic hydrocarbon grouphaving 3 to 6 carbon atoms having at least one double bond.Representative examples of such alkenyl groups include ethenyl,propenyl, butenyl and cyclohexenyl. References to “halo(C₂-C₆) alkenyl”mean a (C₂-C₆) alkenyl group substituted by one or more halogen atoms asherein defined.

References herein to “(C₂-C₆) alkynyl” means any linear, or branchedhydrocarbon groups of 2 to 6 carbon atoms, having at least one triplebond. Representative examples of such alkynyl groups include ethynyl,propargyl and butynyl. References to “halo(C₂-C₆) alkynyl” mean a(C₂-C₆) alkynyl group substituted by one or more halogen atoms as hereindefined.

Illustrative examples of Het within the definition of R1 and R5 includethose selected from the group comprising furyl, tetrahydrofuryl,benzofuryl, tetrahydrobenzofuryl, thienyl, tetrahydrothienyl,benzothienyl, tetrahydrobenzo-thienyl, pyrrolyl, pyrrolidinyl, indolyl,indolinyl, tetrahydroindolyl, oxazolyl, oxazolinyl, oxazolidinyl,benzoxazolyl, tetrahydrobenzoxazolyl, oxazolopyridinyl,tetrahydrooxazolopyridinyl, oxazolopyrimidinyl,tetrahydrooxazolopyrimidinyl, oxazolopyrazinyl, oxazolopyridazinyl,oxazolotriazinyl, isoxazolyl, benzoisoxazolyl,tetrahydrobenzoisoxazolyl, thiazolyl, thiazolinyl, thiazolidinyl,benzothiazolyl, tetra-hydrobenzothiazolyl, thiazolopyridinyl,tetrahydrothiazolopyridinyl, thiazolopyri-midinyl,tetrahydrothiazolopyrimidinyl, thiazolopyrazinyl, thiazolopyridazinyl,thia-zolotriazinyl, isothiazolyl, benzoisothiazolyl,tetrahydrobenzoisothiazolyl, imidazolyl, benzimidazolyl,tetrahydrobenzimidazolyl, pyrazolyl, indazolyl, tetrahydroindazolyl,triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyranyl,dihydropyranyl, tetrahydropyranyl, benzopyranyl, dioxanyl,benzodioxanyl, dioxolanyl, benzodioxolanyl, pyridinyl, pyridonyl,piperidinyl, tetrahydropyridinyl, quinolinyl, isoquinolinyl, tetra- andperhydro-quinolinyl and isoquinolinyl, pyrimidinyl, quinazolinyl,pyrazinyl, pyrazidinyl, piperazinyl, quinoxalinyl, piridazinyl,cinnolinyl, phtalazinyl, triazinyl, purinyl, pyrazolopyridinyl,tetrahydropyrazolopyridnyl, pyrazolopyrimidinyl, pyrazolopyrazinyl,pyrazolotriazinyl, triazolopyridinyl, tetra-hydrotriazolopyridinyl,triazolopyrimidinyl, triazolopyrazinyl, triazolotriazinyl, oxetanyl,azetidinyl and morpholinyl.

Illustrative examples of saturated nitrogen containing heterocycleswithin the definition of NR_(a)R_(b) include those selected from thegroup comprising, pyrrolidinyl, oxazolidinyl, thiazolidinyl,piperidinyl, piperazinyl and morpholinyl.

In one embodiment, W and X both represent CH₂, thus forming anazetidinyl ring which is substituted at the 3 position by R1 and R2.

In an alternative embodiment, one of W and X represents CH₂ and theother represents CH₂CH₂, thus forming a pyrrolidinyl ring which issubstituted at the 3 position by R1 and R2.

In an alternative embodiment, one of W and X represents a bond and theother represents CH₂CH₂CH₂, thus forming a pyrrolidinyl ring which issubstituted at the 2 position by R1 and R2.

In a further alternative embodiment, W and X both represent CH₂CH₂, thusforming a piperidinyl ring which is substituted at the 4 position by R1and R2.

In a further alternative embodiment, one of W and X represents CH₂ andthe other represents CH₂CH₂, thus forming a piperidinyl ring which issubstituted at the 3 position by R1 and R2.

In a yet further alternative embodiment, one of W and X represents abond and the other represents CH₂CH₂CH₂CH₂, thus forming a piperidinylring which is substituted at the 2 position by R1 and R2.

In a most particular embodiment, W and X both represent CH₂, thusforming an azetidinyl ring which is substituted at the 3 position by R1and R2.

In one embodiment, R1 represents an H, F, (C₁-C₆) alkyl, (C₂-C₆)alkenyl, OR_(d), S(O)_(n)R_(a), —C(R_(a))═N—O—R_(f), Y—Ar or Z-Het groupeach of which may be optionally substituted by one or more R4 groups.

In a further embodiment, R1 represents an H, F, (C₁-C₆) alkyl, (C₂-C₆)alkenyl, OR_(d), S(O)_(n)R_(a), Y—Ar or Z-Het group each of which may beoptionally substituted by one or more R4 groups.

In a yet further embodiment, R1 represents an H, (C₁-C₆) alkyl, OR_(d),S(O)_(n)R_(a), Y—Ar or Z-Het group each of which may be optionallysubstituted by one or more R4 groups.

In a still yet further embodiment, R1 represents OR_(d), Z-Het or—C(R_(a))═N—O—R_(f), such as a Z-Het group (i.e. benzofuranyl optionallysubstituted by a methyl group).

In one embodiment, R1 represents H.

When R1 represents (C₁-C₆) alkyl optionally substituted by one or moreR4 groups, in one embodiment R1 represents ethyl or propyl optionallysubstituted by one or more OR_(d) groups (such as —OH). In a furtherembodiment, R1 represents propyl or ethyl substituted by an OH group. Ina yet further embodiment, R1 represents propyl or (CH₂)₂OH.

When R1 represents OR_(d), in one embodiment R_(d) represents (C₁-C₆)alkyl (e.g. butyl, pentyl or —(CH₂)₂—CH(Me)), halo(C₁-C₆) alkyl (e.g.—CH₂—CF₃ or —CH₃—CF₃), —(C₁-C₆) alkyl-O—(C₁-C₆) alkyl (e.g. —(CH₂)₂—OMeor —(CH₂)₃—OMe) or (C₂-C₆) alkenyl (e.g. —CH₂—CH═CH-Me or—CH₂—C(Me)=CH-Me).

When R1 represents OR_(d), in a further embodiment R_(d) represents(C₁-C₆) alkyl, such as pentyl or (C₂-C₆) alkenyl such as —CH₂—CH═CH-Me.

When R1 represents OR_(d), in a yet further embodiment R_(d) represents(C₁-C₆) alkyl, such as butyl.

When R1 represents S(O)_(n)R_(a), in one embodiment n represents 2 andR_(a) represents (C₁-C₆) alkyl, such as pentyl.

When R1 represents Y—Ar, in one embodiment, R1 represents phenyl,—O-phenyl, —O—CH₂-phenyl or —CH₂—O-phenyl each of which may beoptionally substituted by one or more R4 groups (such as—CH₂—O-fluorophenyl).

In one embodiment, Ar represents phenyl.

In one embodiment, Y represents a bond or a linker selected from O or—O—(C₁-C₆) alkylene (such as —O—CH₂— or —CH₂—O—).

When R1 represents Z-Het, in one embodiment, R1 represents benzoxazolyl,oxadiazolyl, benzofuranyl, —S-thienyl, —O-benzothiophenyl,—O-benzofuranyl, —O-pyridyl, —O—CH₂-pyridyl, —O—CH₂-thienyl,—O—(CH₂)₂-thienyl, —O—(CH₂)₃-thienyl, —O—CH₂-thiazolyl,—O—CH₂-pyrazolyl, —O—CH₂-furanyl, —O—CH₂-benzothiophenyl, or—ON═C(Me)-CH₂-pyrimidinyl each of which may be optionally substituted byone or more R4 groups.

When R1 represents Z-Het, in a further embodiment, R1 representsbenzoxazolyl, oxadiazolyl, —O-pyridyl, —O—CH₂-pyridyl, —O—CH₂-thienyl,—O—CH₂-thiazolyl or —ON═C(Me)-CH₂-pyrimidinyl each of which may beoptionally substituted by one or more R4 groups (such asmethyloxadiazolyl).

When R1 represents Z-Het, in a yet further embodiment, R1 represents—O—CH₂-thienyl, —O—(CH₂)₂-thienyl or -benzofuranyl optionallysubstituted by an R4 group (such as methyl).

When R1 represents Z-Het, in a still yet further embodiment, R1represents -benzofuranyl optionally substituted by an R4 group (such asmethyl).

When R1 represents —C(R_(a))═N—O—R_(f), in one embodiment, R_(a)represents (C₁-C₆) alkyl (e.g. methyl) and R_(f) represents (C₁-C₆)alkyl (e.g. ethyl or propyl), halo(C₁-C₆) alkyl (e.g. —CH₂—CF₃) or—(C₁-C₆) alkyl-Ar (e.g. —CH₂-phenyl).

When R1 represents —C(R_(a))═N—O—R_(f), in a further embodiment, R_(a)represents (C₁-C₆) alkyl (e.g. methyl) and R_(f) represents (C₁-C₆)alkyl (e.g. propyl).

In one embodiment, Het represents benzothiophenyl, benzofuranyl,benzoxazolyl, oxadiazolyl, pyridyl, pyrazolyl, thienyl, thiazolyl,furanyl or pyrimidinyl each of which may be optionally substituted byone or more R4 groups.

In a further embodiment, Het represents benzoxazolyl, oxadiazolyl,pyridyl, thienyl, thiazolyl or pyrimidinyl each of which may beoptionally substituted by one or more R4 groups.

In one embodiment, Z represents a bond or a linker selected from O, S or—O—(C₁-C₆) alkylene (such as —O—CH₂—, —O—(CH₂)₂— or —O—(CH₂)₃—) or—ON—CR_(d)—(C₁-C₆) alkylene (such as —ON═C(Me)-CH₂—).

In a further embodiment, Z represents a bond or a linker selected from Oor —O—(C₁-C₆) alkylene (such as —O—CH₂—) or —ON═CR_(d)—(C₁-C₆) alkylene(such as —ON═C(Me)-CH₂—).

In one embodiment, R1 represents OR_(d) (such as —O-pentyl) or Z-Het(such as —O—CH₂-thienyl). In a further embodiment, R1 represents Z-Het,such as —O—CH₂-thienyl.

In one embodiment, R2 represents an H or OR_(d) group. In a furtherembodiment, R2 represents an H or OH group. In a yet further embodiment,R2 represents H.

In one embodiment, R4 represents halogen (such as bromine, chlorine orfluorine), (C₁-C₆) alkyl (such as methyl), (C₂-C₆) alkenyl or (C₂-C₆)alkynyl. In a further embodiment, R4 represents halogen (such asfluorine) or (C₁-C₆) alkyl (such as methyl). In a yet furtherembodiment, R4 represents fluorine or methyl.

In a further embodiment, R4 represents halogen (such as fluorine),(C₁-C₆) alkyl (such as methyl), (C₂-C₆) alkenyl or (C₂-C₆) alkynyl. In afurther embodiment, R4 represents halogen (such as fluorine) or (C₁-C₆)alkyl (such as methyl). In a yet further embodiment, R4 representsfluorine or methyl.

Examples of ring systems within the definition of R3 includeheterocycles of formula (a)-(i):

each of which may be optionally substituted, or further substituted asappropriate, by one or more R5 groups.

An example of a compound of formula (I) wherein two R5 groups togetherwith the atom to which they are attached together form a Het groupoptionally substituted by one or more (C₁-C₆) alkyl groups include aspiro ring system of formula (j):

A further examples of a ring system within the definition of R3 includesthe heterocycle of formula (k):

which may be optionally substituted, or further substituted asappropriate, by one or more R5 groups.

In one embodiment, R3 is a pyridyl ring or a pyridyl ring fused to a 5,6 or 7 membered aromatic, partially aromatic or saturated heterocyclecontaining 1-5 heteroatoms selected from N, O and S, wherein said R3group may be optionally substituted by one or more R5 groups.

In a further embodiment, R3 is a pyridyl ring or a pyridyl ring fused toa 5 or 6 membered aromatic, partially aromatic or saturated heterocyclecontaining 1-5 heteroatoms selected from N, O and S, wherein said R3group may be optionally substituted by one or more R5 groups.

In a yet further embodiment, R3 is a pyridyl ring or a pyridyl ringfused to a 6 membered aromatic, partially aromatic or saturatedheterocycle containing 1-5 heteroatoms selected from N, O and S, whereinsaid R3 group may be optionally substituted by one or more R5 groups.

In a still yet further embodiment, R3 is a pyridyl ring fused to a 6membered aromatic, partially aromatic or saturated heterocyclecontaining 1-5 heteroatoms selected from N, O and S, wherein said R3group may be optionally substituted by one or more R5 groups.

In one embodiment, R3 represents a heterocycle of formula (k):

which may be optionally substituted, or further substituted asappropriate, by one or more R5 groups, such as (C₁-C₆) alkyl optionallysubstituted by CO₂R_(d) (e.g. —CH₂—CO₂H), NR_(a)R_(b) (e.g. —CH₂—N(Me)₂)or Het optionally substituted by one or more (C₁-C₆) alkyl groups (e.g.—(CH₂)₂-piperazinyl-Me).

In one embodiment, R3 represents a heterocycle of formula (a), (b), (c),(d), (f), (i), (j) or (k):

each of which may be optionally substituted, or further substituted asappropriate, by one or more R5 groups, such as CO₂R_(d) (e.g. CO₂Me),NR_(a)R_(b) (e.g. NH₂), CONR_(a)R_(b) (e.g. CONH₂), NR_(c)COR_(d) (e.g.NHCOMe) or (C₁-C₆) alkyl optionally substituted by F, CO₂R_(d) (e.g.—CH₂—CO₂H), CONR_(a)R_(b), OR_(d) (e.g. CH₂OH), NR_(a)R_(b) (e.g.—CH₂—N(Me)₂), NR_(a)COR_(d) or Het optionally substituted by one or more(C₁-C₆) alkyl groups (e.g. —(CH₂)₂-piperazinyl-Me).

In a further embodiment, R3 represents a heterocycle of formula (a) or(j):

each of which may be optionally substituted, or further substituted asappropriate, by one or more R5 groups, such as CO₂R_(d) (e.g. CO₂Me),NR_(a)R_(b) (e.g. NH₂), CONR_(a)R_(b) (e.g. CONH₂), NR_(c)COR_(d) (e.g.NHCOMe) or (C₁-C₆) alkyl optionally substituted by F, CO₂R_(d) (e.g.—CH₂—CO₂H), CONR_(a)R_(b), OR_(d) (e.g. CH₂OH), NR_(a)R_(b) (e.g.—CH₂—N(Me)₂), NR_(a)COR_(d) or Het optionally substituted by one or more(C₁-C₆) alkyl groups (e.g. —(CH₂)₂-piperazinyl-Me).

In a further embodiment, R3 represents a heterocycle of formula (a), (b)or (c):

each of which may be optionally substituted, or further substituted asappropriate, by one or more R5 groups, such as CO₂R_(d) (e.g. CO₂Me),NR_(a)R_(b) (e.g. NH₂), CONR_(a)R_(b) (e.g. CONH₂), NR_(c)COR_(d) (e.g.NHCOMe) or (C₁-C₆) alkyl optionally substituted by F, CO₂R_(d),CONR_(a)R_(b), OR_(d) (e.g. CH₂OH), NR_(a)R_(b) or NR_(a)COR_(d).

In a further embodiment, R3 represents a heterocycle of formula (c):

optionally substituted by one or more R5 groups, such as NR_(a)R_(b)(e.g. 2-NH₂) or NR_(c)COR_(d) (e.g. 2-NHCOMe).

In a yet further embodiment, R3 represents a heterocycle of formula (a)or (b):

optionally further substituted by one or more R5 groups, such asCO₂R_(d) (e.g. 3-CO₂Me), CONR_(a)R_(b) (e.g. 3-CONH₂) or (C₁-C₆) alkyloptionally substituted by OR_(d) (e.g. 3-CH₂OH).

In a yet further embodiment, R3 represents a heterocycle of formula (a):

optionally further substituted by one or more R5 groups, such asCO₂R_(d) (e.g. 3-CO₂Me), CONR_(a)R_(b) (e.g. 3-CONH₂) or (C₁-C₆) alkyloptionally substituted by OR_(d) (e.g. 3-CH₂OH).

In a still yet further embodiment, R3 represents a heterocycle offormula (a):

which has no further R5 substituents.

In one embodiment, n represents 1 or 2. In a further embodiment, nrepresents 2.

In one embodiment, R_(a), R_(b) and R_(c) independently represent H,(C₁-C₆) alkyl, or an NR_(a)R_(b) group may optionally form a 3- to7-membered nitrogen containing saturated heterocycle optionallycontaining 1 to 3 additional heteroatoms selected from N, O or S whereinsaid heterocycle may be optionally substituted by one or more (C₁-C₆)alkyl groups.

In one embodiment, R_(d) and R_(e) independently represent H, (C₁-C₆)alkyl, (C₂-C₆) alkenyl, halo(C₁-C₆) alkyl, halo(C₁-C₆) alkyl-O—(C₁-C₆)alkyl- or (C₁-C₆) alkyl-O—(C₁-C₆) alkyl-.

In a further embodiment, R_(d) and R_(e) independently represent H,(C₁-C₆) alkyl, halo(C₁-C₆) alkyl-O—(C₁-C₆) alkyl- or (C₁-C₆)alkyl-O—(C₁-C₆) alkyl-.

In one embodiment, R_(f) represents (C₁-C₆) alkyl (e.g. ethyl orpropyl), halo(C₁-C₆) alkyl (e.g. —CH₂—CF₃) or —(C₁-C₆) alkyl-Ar (e.g.—CH₂-phenyl).

In one embodiment, the compound of formula (I) is selected from:

-   6-[(1E)-3-Azetidin-1-yl-3-oxoprop-1-en-1-yl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E1);-   6-[(1E)-3-Oxo-3-pyrrolidin-1-ylprop-1-en-1-yl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E2);-   6-[(1E)-3-Oxo-3-piperidin-1-ylprop-1-en-1-yl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E3);-   6-{(1E)-3-[4-(2-Hydroxyethyl)piperidin-1-yl]-3-oxoprop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E4);-   6-[(1E)-3-{[4-(4-Fluorophenoxy)methyl]piperidin-1-yl}-3-oxoprop-1-en-1-yl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E5);-   6-[(1E)-3-Oxo-3-(3-phenoxyazetidin-1-yl)prop-1-en-1-yl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E6);-   6-[(1E)-3-Oxo-3-(2-phenylpyrrolidin-1-yl)prop-1-en-1-yl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E7);-   6-[(1E)-3-Oxo-3-(4-propylpiperidin-1-yl)prop-1-en-1-yl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E8);-   6-[(1E)-3-{[3-(4-Fluorophenoxy)methyl]piperidin-1-yl}-3-oxoprop-1-en-1-yl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E9);-   6-[(1E)-3-Oxo-3-(3-phenoxypyrrolidin-1-yl)prop-1-en-1-yl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E10);-   6-{(1E)-3-[3-(5-Methyl-1,2,4-oxadiazol-3-yl)azetidin-1-yl}-3-oxoprop-1-en-1-yl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E11);-   6-{(1E)-3-Oxo-3-[3-(2-thienylmethoxy)azetidin-1-yl]prop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E12);-   6-{(1E)-3-[2-(5-Methyl-1,2,4-oxadiazol-3-yl)piperidin-1-yl]-3-oxoprop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E13);-   6-{(1E)-3-[4-Hydroxy-4-phenylpiperidin-1-yl]-3-oxoprop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E14);-   6-{(1E)-3-Oxo-3-[3-(pentyloxy)azetidin-1-yl]prop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E15);-   6-{(1E)-3-Oxo-3-[3-(pyridin-3-yloxy)pyrrolidin-1-yl]prop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E16);-   6-{(1E)-3-[3-(Benzyloxy)azetidin-1-yl]-3-oxoprop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E17);-   6-{(1E)-3-[2-(1,3-Benzoxazol-2-yl)piperidin-1-yl]-3-oxoprop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E18);-   6-[(1E)-3-{3-[(2-Methylprop-2-en-1-yl)oxy]azetidin-1-yl}-3-oxoprop-1-en-1-yl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E19);-   6-{(1E)-3-Oxo-3-[3-(1,3-thiazol-2-ylmethoxy)azetidin-1-yl]prop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E20);-   6-{(1E)-3-[3-({[(1E)-1-Methyl-2-pyrimidin-2-ylethylidene]amino}oxy)azetidin-1-yl]-3-oxoprop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E21);-   6-{(1E)-3-[3-(Pentylsulfonyl)azetidin-1-yl]-3-oxoprop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E22);-   5-{(1E)-3-Oxo-3-[3-(pyridin-4-ylmethoxy)azetidin-1-yl]prop-1-en-1-yl}pyridin-2-amine    (E23);-   N-(5-{(1E)-3-Oxo-3-[3-(pyridin-4-ylmethoxy)azetidin-1-yl]prop-1-en-1-yl}pyridin-2-yl)acetamide    (E24);-   Methyl    6-[(1E)-3-{4-[(4-fluorophenoxy)methyl]piperidin-1-yl}-3-oxoprop-1-en-1-yl]-2-oxo-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate    (E25);-   6-[(1E)-3-{4-[(4-Fluorophenoxy)methyl]piperidin-1-yl}-3-oxoprop-1-en-1-yl]-2-oxo-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxamide    (E26);-   6-[(1E)-3-{4-[(4-Fluorophenoxy)methyl]piperidin-1-yl}-3-oxoprop-1-en-1-yl]-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide    (E27); and-   3-(Hydroxymethyl)-6-[(1E)-3-{4-[(4-fluorophenoxy)methyl]piperidin-1-yl}-3-oxoprop-1-en-1-yl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E28);    or a pharmaceutically acceptable salt or solvate thereof.

In an alternative embodiment, the compound of formula (I) is selectedfrom:

-   (E)-6-(3-Oxo-3-(3-(2-(thiophen-2-yl)ethoxy)azetidin-1-yl)prop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E29);-   (E)-6-(3-Oxo-3-(3-(3-(thiophen-2-yl)propoxy)azetidin-1-yl)prop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E30);-   (E)-6-(3-(3-((3-Methylthiophen-2-yl)methoxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E31);-   6-[3-(3-(4-Methyl-thiophen-2ylmethoxy)-azetidin-1-yl)-3-oxo-propenyl]-3,4-dihydro-1H-[1,8]naphthyridin-2-one    (E32);-   (E)-6-(3-(3-((5-Methylthiophen-2-yl)methoxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E33);-   (E)-6-[3-(2-Methoxyethoxyl)azetidin-1-yl)-3-oxoprop-1-enyl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E34);-   (E)-6-[3-(3-Methoxypropoxy)azetidin-1-yl)-3-oxoprop-1-enyl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E35);-   (E)-6-[3-(3-Butoxyazetidin-1-yl)-3-oxoprop-1-enyl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E36);-   (E)-6-[3-(3-Isobutoxyazetidin-1-yl)-3-oxoprop-1-enyl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E37);-   (E)-6-(3-(3-((1-Methyl-1H-pyrazol-3-yl)methoxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E38);-   (E)-6-(3-Oxo-3-(3-(thiazol-5-ylmethoxy)azetidin-1-yl)prop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E39);-   (E)-6-(3-(3-(Furan-2-ylmethoxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E40);-   (E)-1′-Methyl-6-(3-oxo-3-(3-(thiophen-2-ylmethoxy)azetidin-1-yl)prop-1-enyl)-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one    (E41);-   (E)-7-(3-Oxo-3-(3-(thiophen-2-ylmethoxy)azetidin-1-yl)prop-1-enyl)-4,5-dihydro-1H-pyrido[2,3-e][1,4]diazepin-2(3H)-one    (E42);-   (E)-Ethyl    2-(2-oxo-6-(3-oxo-3-(3-(thiophen-2-ylmethoxy)azetidin-1-yl)prop-1-enyl)-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)acetate    (E43);-   (E)-3-(2-(4-Methylpiperazin-1-yl)ethyl)-6-(3-oxo-3-(3-(thiophen-2-ylmethoxy)azetidin-1-yl)prop-1-enyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one    (E44);-   (E)-3-(3-((Dimethylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(3-(thiophen-2-ylmethoxy)azetidin-1-yl)prop-2-en-1-one    (E45);-   (E)-6-(3-Oxo-3-(3-(thiophen-2-ylmethoxy)azetidin-1-yl)prop-1-enyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one    (E46);-   (E)-6-(3-Oxo-3-(3-(3,3,3-trifluoropropoxy)azetidin-1-yl)prop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E47);-   (E)-6-(3-Oxo-3-(3-(4,4,4-trifluorobutoxy)azetidin-1-yl)prop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E48);-   6-((E)-3-(3-((E)-But-2-enyloxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E49);-   6-((E)-3-(3-((Z)-But-2-enyloxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E50);-   6-((E)-3-(3-((E)-2-Methylbut-2-enyloxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E51);-   (E)-6-(3-(3-(Benzo[b]thiophen-2-ylmethoxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E52);-   (E)-6-(3-(3-((4-Bromothiophen-2-yl)methoxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E53);-   (E)-6-(3-(3-((4-Chlorothiophen-2-yl)methoxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E54);-   6-((E)-3-Oxo-3-(3-((Z)-1-(propoxyimino)ethyl)azetidin-1-yl)prop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E55);-   6-((E)-3-Oxo-3-(3-((Z)-1-(2,2,2-trifluoroethoxyimino)ethyl)azetidin-1-yl)prop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E56);-   6-((E)-3-(3-((Z)-1-(Ethoxyimino)ethyl)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E57);-   (E)-6-(3-(3-(Benzofuran-3-yl)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E58);-   (E)-6-(3-(3-(Benzofuran-2-yl)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E59);-   (E)-6-(3-(3-(Benzofuran-7-yloxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E60);-   (E)-6-(3-(3-(Benzo[b]thiophen-3-yloxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E61);-   (E)-6-(3-Oxo-3-(3-(thiophen-2-ylthio)azetidin-1-yl)prop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E62);-   (E)-6-(3-(3-Butoxyazetidin-1-yl)-3-oxoprop-1-enyl)-V-methyl-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one    (E63);-   1′-Methyl-6-((E)-3-oxo-3-(3-((E)-1-(benzyloxyimino)ethyl)azetidin-1-yl)prop-1-enyl)-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one    (E64);-   1′-Methyl-6-((E)-3-oxo-3-(3-((E)-1-(propoxyimino)ethyl)azetidin-1-yl)prop-1-enyl)-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one    (E65);-   (E)-1′-Methyl-6-(3-oxo-3-(3-(2-(thiophen-2-yl)ethoxy)azetidin-1-yl)prop-1-en-1-yl)-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one    (E66);-   (E)-6-(3-(3-(3-Methylbenzofuran-2-yl)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E67);-   (E)-1′-Methyl-6-(3-(3-(3-methylbenzofuran-2-yl)azetidin-1-yl)-3-oxoprop-1-enyl)-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one    (E68);-   (E)-6-(3-(3-(Benzofuran-2-yl)azetidin-1-yl)-3-oxoprop-1-en-1-yl)-V-methyl-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one    (E69);-   6-((E)-3-Oxo-3-(3-((E)-1-(propoxyimino)ethyl)azetidin-1-yl)prop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E70); and-   6-((E)-3-Oxo-3-(3-((Z)-1-(propoxyimino)ethyl)azetidin-1-yl)prop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E71);    or a pharmaceutically acceptable salt or solvate thereof.

In a further embodiment, the compound of formula (I) is selected from6-{(1E)-3-Oxo-3-[3-(2-thienylmethoxy)azetidin-1-yl]prop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E12) or6-{(1E)-3-Oxo-3-[3-(pentyloxy)azetidin-1-yl]prop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E15) or a pharmaceutically acceptable salt or solvate thereof.

In a further embodiment, the compound of formula (I) is selected from

-   6-{(1E)-3-Oxo-3-[3-(2-thienylmethoxy)azetidin-1-yl]prop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E12);-   (E)-6-(3-Oxo-3-(3-(2-(thiophen-2-yl)ethoxy)azetidin-1-yl)prop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E29);-   (E)-6-(3-(3-(Benzofuran-2-yl)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E59);-   (E)-6-(3-(3-Butoxyazetidin-1-yl)-3-oxoprop-1-enyl)-V-methyl-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one    (E63);-   (E)-1′-Methyl-6-(3-oxo-3-(3-(2-(thiophen-2-yl)ethoxy)azetidin-1-yl)prop-1-en-1-yl)-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one    (E66);-   (E)-6-(3-(3-(3-Methylbenzofuran-2-yl)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E67);-   (E)-1′-Methyl-6-(3-(3-(3-methylbenzofuran-2-yl)azetidin-1-yl)-3-oxoprop-1-enyl)-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one    (E68);-   (E)-6-(3-(3-(Benzofuran-2-yl)azetidin-1-yl)-3-oxoprop-1-en-1-yl)-V-methyl-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one    (E69);-   6-((E)-3-Oxo-3-(3-((E)-1-(propoxyimino)ethyl)azetidin-1-yl)prop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E70); and-   6-((E)-3-Oxo-3-(3-((Z)-1-(propoxyimino)ethyl)azetidin-1-yl)prop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E71);    or a pharmaceutically acceptable salt or solvate thereof.

In a further embodiment, the compound of formula (I) is selected from6-{(1E)-3-Oxo-3-[3-(2-thienylmethoxy)azetidin-1-yl]prop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E12) or a pharmaceutically acceptable salt or solvate thereof.

In a yet further embodiment, the compound of formula (I) is selectedfrom

-   (E)-6-(3-(3-(Benzofuran-2-yl)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E59); and-   (E)-6-(3-(3-(3-Methylbenzofuran-2-yl)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one    (E67);    or a pharmaceutically acceptable salt or solvate thereof.

The compounds of formula (I) and their salts may be prepared byprocesses known to the skilled chemist to be applicable for preparingchemically related compounds. Such processes use known startingmaterials or intermediates which may be obtained by standard proceduresof organic chemistry. The following processes provide a variety ofnon-limiting routes for the production of the compounds of formula (I)and their intermediates used therein. These processes constitute furtheraspects of the invention.

According to a further aspect of the invention, there is provided aprocess for preparing a compound of formula (I) as defined above whichcomprises:

(a) reacting a compound of formula (II):

wherein R3 is as defined above for compounds of formula (I), with acompound of formula (III):

wherein W, X, R1 and R2 are as defined above for compounds of formula(I); or(b) reacting a compound of formula (IV):

wherein R3 is as defined above for compounds of formula (I) and L¹represents a suitable leaving group, such as a halogen atom, e.g.fluorine, chlorine, bromine or an alkoxy group, with a compound offormula (III):

wherein W, X, R1 and R2 are as defined above for compounds of formula(I); or(c) reacting a compound of formula (V):

wherein W, X, R1 and R2 are as defined above for compounds of formula(I), with a compound of formula L²-R3, wherein L² represents a suitableleaving group, such as a halogen atom, e.g. fluorine, chlorine, bromineor an alkoxy group; optionally thereafter followed by:(d) deprotecting a protected derivative of compound (I); and optionallythereafter followed by:(e) interconversion of a compound of formula (I) to a further compoundof formula (I).

Process (a) typically comprises the use of EDC, a base such as TEA orDIPEA or DMAP, the optional use of HOBT, and a solvent such as DMF.

Process (b) typically comprises the use of a base such as TEA or DIPEAor DMAP, and a solvent such as DCM, THF, ACN or DMF.

Process (c) typically comprises the use of suitable coupling conditionsknown to the one skilled in the art such as the Heck coupling (Chem.Rev. 2000, 100, 3009), a non-limiting example comprises the use of apalladium catalyst, a phosphine ligand, a suitable base and solvent.

Process (d) typically comprises any suitable deprotection reaction, theconditions of which will depend upon the nature of the protecting group.In most instances such a deprotection reaction will typically comprisethe use of a suitable acid.

Process (e) typically comprises interconversion procedures known by oneskilled in the art. For example, compounds of formula (I) in which R1 orR2 represents hydrogen may be converted by methods known by one skilledin the art into compounds of formula (I) in which R1 or R2 representsCO₂R_(a), COR_(a), CONR_(a)R_(b), CH₂OR_(c), CH₂NR_(a)R_(b),SO₂NR_(a)R_(b), wherein R_(a), R_(b) and R_(c) are as defined above forcompounds of formula (I).

If appropriate, the reactions previously described in processes (a),(b), (c), (d) or (e) are followed or preceded by one or more reactionsknown to the skilled of the art and are performed in an appropriateorder to achieve the requisite substitutions on W, X, R1, R2 and R3defined above to afford other compounds of formula (I). Non-limitingexamples of such reactions whose conditions can be found in theliterature include:

-   -   protection of reactive functions,    -   deprotection of reactive functions,    -   halogenation,    -   dehalogenation,    -   dealkylation,    -   alkylation of amine, aniline, alcohol and phenol,    -   Mitsunobu reaction on hydroxyl groups,    -   cycloaddition reactions on appropriate groups,    -   reduction of nitro, esters, cyano, aldehydes,    -   transition metal-catalyzed coupling reactions,    -   acylation,    -   sulfonylation/introduction of sulfonyl groups,    -   saponification/hydrolysis of esters groups,    -   amidification or transesterification of ester groups,    -   esterification or amidification of carboxylic groups,    -   halogen exchange,    -   nucleophilic substitution with amine, thiol or alcohol,    -   reductive amination,    -   oxime formation on carbonyl and hydroxylamine groups,    -   S-oxidation,    -   N-oxidation,    -   salification.

The compounds of formula (II), (III), (IV), (V) and L²-R3 are eitherknown or may be prepared in accordance with known procedures such asthose described herein.

As illustrated by the examples given below, the hereinbefore disclosedcompounds of formula (I) have valuable biological properties. They areparticularly useful as antibacterial agents having a selective spectrumof activity in vitro and in vivo against bacterial strains relying onFabI and related targets. Such strains encompass Staphylococcus aureusincluding multiresistant strains (such as methicillin-susceptibleStaphylococcus aureus (MSSA), methicillin-resistant Staphylococcusaureus (MRSA), vancomycin-intermediate Staphylococcus aureus (VISA) andvancomycin-resistant Staphylococcus aureus (VRSA) strains),Acinetobacter baumannii, Bacillus anthracis, Chlamydophila pneumoniae,Escherichia coli, Haemophilus influenzae, Helicobacter pylori,Klebsiella pneumoniae, Neisseria meningitidis and also bacteria such asMycobacterium tuberculosis carrying homologous FabI enzymes such as InhAor other organisms such as Plasmodium falciparum. In one embodiment, thecompound of the invention is used in the treatment of Staphylococcusaureus microbial infections including multiresistant strains such asmethicillin-susceptible Staphylococcus aureus (MSSA),methicillin-resistant Staphylococcus aureus (MRSA),vancomycin-intermediate Staphylococcus aureus (VISA) andvancomycin-resistant Staphylococcus aureus (VRSA) strains.

The compounds of formula (I) are therefore particularly suitable asactive principles of a medicament.

According to a further aspect of the invention, there is provided acompound of formula (I) as hereinbefore defined for use in therapy.

According to a further aspect of the invention, there is provided apharmaceutical composition comprising a compound of formula (I) ashereinbefore defined, in association with a pharmaceutically acceptableexcipient or carrier.

Said pharmaceutical compositions are advantageously formulated to beadministered under oral, topical, parental including injectable routes,such as intravenous administration, with individual doses appropriatefor the patient to be treated.

The compositions according to the invention can be solid, liquid or inthe form of a gel/cream and be present in the pharmaceutical formscommonly used in human medicine, such as for example, plain orsugar-coated tablets, gelatin capsules, granules, suppositories,injectable preparations, ointments, creams, gels; they are preparedaccording to the customary methods. The active ingredient/s can beincorporated using excipients which are customarily used in thesepharmaceutical compositions, such as talc, gum arabic, lactose, starch,magnesium stearate, aqueous or non-aqueous vehicles, fatty substances ofanimal or vegetable origin, paraffin derivatives, glycols, variouswetting agents, dispersants or emulsifiers, preservatives. Thesecompositions can also be present in the form of a powder intended to bedissolved extemporaneously in an appropriate vehicle, for example,non-pyrogenic sterile water.

The dose administered varies according to the condition treated, thepatient in question, the administration route and the product envisaged.It can, for example, be comprised between 0.01 g and 10 g per day, byoral route or by intramuscular or intravenous route in humans.

Said compositions are particularly useful to treat human or animalinfections by microbial pathogens such as Staphylococcus aureusincluding multiresistant strains, Acinetobacter baumannii, Bacillusanthracis, Chlamydophila pneumoniae, Escherichia coli, Haemophilusinfluenzae, Helicobacter pylori, Klebsiella pneumoniae, Neisseriameningitidis, S. intermedius, P. multocida, B. bronchiseptica, M.haemolytica and A. pleuropneumoniae. and also bacteria such asMycobacterium tuberculosis or other organisms such as Plasmodiumfalciparum.

Said compositions can also be useful in multitherapy, in combinationwith other medicaments, for example with antibiotics. It will beappreciated that such multitherapy may typically comprise either acomposition comprising the compound of formula (I) additionallycomprising one or more other medicaments, such as antibiotics orco-administration (i.e. sequential or simultaneous administration).

The invention therefore also relates to a method of treatment ofmicrobial infections which comprises administering to a patient in needthereof an efficient amount of a compound of formula (I) as hereinbeforedefined.

The invention also relates to a compound of formula (I) as hereinbeforedefined for use in the treatment of microbial infections.

The invention also relates to the use of a compound of formula (I) ashereinbefore defined in the manufacture of a medicament for thetreatment of microbial infections.

The invention also relates to a pharmaceutical composition comprising acompound of formula (I) as hereinbefore defined for use in the treatmentof microbial infections.

EXAMPLES

Proton nuclear magnetic resonance (¹H NMR) spectra were recorded on a400 MHz Brüker instrument, and chemical shifts are reported in parts permillion downfield from the internal standard tetramethylsilane (TMS).Abbreviations for NMR data are as follows: s=singlet, d=doublet,t=triplet, q=quadruplet, m=multiplet, dd=doublet of doublets, dt=doubletof triplets, br=broad. J indicates the NMR coupling constant measured inHertz. CDCl₃ is deuteriochloroform, DMSO-d₆ ishexadeuteriodimethylsulfoxide, and CD₃OD is tetradeuteriomethanol. Massspectra were obtained using electrospray ionization (ESI) techniques onan Agilent 1100 Series LCMS. Analtech Silica Gel GF and E. Merck SilicaGel 60 F-254 thin layer plates were used for thin layer chromatography.Flash chromatography was carried out on Flashsmart Pack cartridgeirregular silica 40-60 μm or spherical silica 20-40 μm. Preparative thinlayer chromatography was carried out on Analtech Silica Gel GF 1000 μm20×20 cm.

The meaning of certain abbreviations is given herein. ESI refers toelectrospray ionization, HPLC refers to high pressure liquidchromatography, LCMS refers to liquid chromatography coupled with a massspectrometer, M in the context of mass spectrometry refers to themolecular peak, MS refers to mass spectrometer, NMR refers to nuclearmagnetic resonance, pH refers to potential of hydrogen, TEA refers totriethylamine, DIPEA refers to N,N-diisopropylethylamine, HOBt refers to1-hydroxybenzotriazole, DCM refers to dichloromethane, EtOAc refers toethyl acetate, DMF refers to N,N-dimethylformamide, EDAC refersN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, DMAP or4-DMAP refers to 4-(dimethylamino)pyridine, TLC refers to thin layerchromatography.

The starting materials are commercially available unless indicatedotherwise.

Intermediate 1(E)-3-(7-Oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acidhydrochloride (D1) Step 1: 2-Amino-3-(hydroxymethyl)pyridine

Lithium aluminum hydride (12.4 g, 326.7 mmol) was portionwisely added toa suspension of 2-amino-3-carboxypyridine (30.0 g, 217.2 mmol) in THF(350 mL) at 0° C. Once the addition was completed, the reaction mixturewas stirred at room temperature for 15 minutes and then at refluxovernight. The mixture was then cooled to 0° C. and hydrolyzed by thesuccessive addition of water (18 mL), a solution of sodium hydroxyde (18mL) and water (30 mL) again. The resulting white suspension was filteredon Clarcel® and the cake was washed with THF (200 mL) and a mixture ofCHCl₃/MeOH (250 mL, 9:1). After concentration to dryness of thefiltrate, the title product was obtained as a yellow solid (24.2 g,90%).

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 7.84 (d, J=4 Hz, 1H), 7.37 (d, J=7.2Hz, 1H), 6.55-6.52 (m, 1H), 5.64 (br s, NH₂), 4.34 (s, 2H).

Step 2: 2-Amino-5-bromo-3-(hydroxymethyl)pyridine

Bromine (8.4 mL, 189.4 mmol) was added dropwise over 1 hour to asolution of 2-amino-3-(hydroxymethyl)pyridine (19.6 g, 157.8 mmol; whichmay be prepared as described in D1, Step 1) in acetic acid (350 mL) atroom temperature. The reaction mixture was then stirred overnight. Afterconcentration to dryness, the residue was partitioned between asaturated solution of potassium carbonate (300 mL) and ethyl acetate(200 mL). The aqueous layer was separated and extracted with ethylacetate (2×200 mL). The combined organic phases were washed with asaturated solution of sodium chloride (200 mL), dried over sodiumsulfate, filtered and concentrated to dryness. After trituration of theresidue in pentane, the title product was obtained as a yellow solid(27.0 g, 84%).

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 7.90 (d, J=2.8 Hz, 1H), 7.53 (d, J=2Hz, 1H), 5.93 (br s, NH₂), 5.29 (br s, OH), 4.31 (s, 2H).

Step 3: 2-Amino-5-bromo-3-(bromomethyl)pyridine hydrobromide

A solution of 2-amino-5-bromo-3-(hydroxymethyl)pyridine (27.0 g, 133.0mmol; which may be prepared as described in D1, Step 2) in hydrobromicacid (48% in H₂O, 72 mL) was stirred at reflux overnight. The reactionmixture was then concentrated to dryness (toluene was used to azeotropethe residual H₂O). The title product was obtained as pale brown solid(47.0 g, 100%) which was used in the next step without furtherpurification.

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 8.1 (d, J=2 Hz, 1H), 7.97 (d, J=2Hz, 1H), 4.41 (s, 2H).

Step 4:6-Bromo-2-oxo-1,2,3,4-tetrahydro-1H-1,8-naphthyridine-3-methylcarboxylate

Dimethylmalonate (32 mL, 276.7 mmol) was added to a solution of sodiummethoxide (25% in methanol, 63 mL, 76.1 mmol) in methanol (150 mL) atroom temperature. After 45 minutes stirring,2-amino-5-bromo-3-(bromomethyl)pyridine hydrobromide (24 g, 69.2 mmol;which may be prepared as described in D1, Step 3) was added to themixture which was stirred at room temperature overnight. A largequantity of water was finally added to the mixture. The formedprecipitate was filtered, washed with petroleum ether and dried underhigh vacuum to afford the title product as a brown solid (16.6 g, 84%).

LCMS (ESI-APCI) m/z 285.0-287.0 (M+H)⁺

Step 5: 6-Bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one

A solution of sodium hydroxide (1N, 248 mL) was added to a suspension of6-bromo-2-oxo-1,2,3,4-tetrahydro-1H-1,8-naphthyridine-3-methylcarboxylate(16.6 g, 58.24 mmol; which may be prepared as described in D1, Step 4)in methanol (620 mL) at room temperature. The reaction mixture was thenrefluxed for 4 hours and cooled down to room temperature. A solution ofhydrochloric acid (1N, 248 mL) was then added and the mixture wasrefluxed overnight. The methanol was removed and the residue filtered.The resulting precipitate was washed with water and dried under highvacuum to afford the title product as a white solid (7.7 g, 58%).

LCMS (ESI-APCI) m/z 227.0-229.0 (M+H)⁺

Step 6:tert-Butyl(E)-3-(7-Oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylate

tert-Butyl acrylate (31.2 mL, 210 mmol), diisopropylethylamine (19.4 mL,110 mmol) and P(o-tolyl)₃ (3.2 g, 10.5 mmol) were successively added toa suspension of 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (11.9 g,52.5 mmol; which may be prepared as described in D1, Step 5) inpropionitrile (83 mL) and dimethylformamide (46 mL). The resultingmixture was then purged with argon prior to the addition of palladiumacetate (1.2 g, 5.2 mmol). The mixture was purged with argon again andrefluxed overnight. The reaction mixture was then filtered on Celite®.The filtrate was concentrated to dryness and the residue was solubilizedin ethyl acetate (200 mL). The resulting solution was washed with asaturated solution of sodium chloride (3×100 mL), dried over sodiumsulfate, filtered and concentrated to dryness. The residue was purifiedby chromatography on silica gel, using dichloromethane/methanol (98:2)as eluent. After trituration with Et₂O/petroleum ether (1/1), the titleproduct was obtained as a yellow solid (4.35 g, 40%).

LCMS (ESI-APCI) m/z 275.0 (M+H)⁺

Step 7: (E)-3-(7-Oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylicacid hydrochloride

Trifluoroacetic acid (31 mL) was added to a suspension oftert-butyl(E)-3-(7-Oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylate(1.1 g, 3.76 mmol; which may be prepared as described in D1, Step 6) indichloromethane (31 mL). The reaction mixture was stirred at roomtemperature for 1 hour and concentrated to dryness. The resultingresidue was solubilized in a solution of hydrochloric acid in dioxane(4N, 60 mL). After 10 minutes stirring at room temperature, theprecipitate was filtered and washed with diethyl ether to afford thetitle product as a pale yellow solid (4.5 g, quantitative).

LCMS (ESI-APCI) m/z 219 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 10.68 (br s, OH), 8.35 (s, 1H), 8.02(s, 1H), 7.54 (d, J=16.0 Hz, 1H), 6.50 (d, J=16.0 Hz, 1H), 2.90 (t,J=7.6 Hz, 2H), 2.50 (t, J=7.6 Hz, 2H). The triplet CH₂ at 2.5 ppm ishidden by DMSO.

Intermediate 2 (E)-Ethyl3-(1′-methyl-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-6-yl)acrylate(D2) Step 1: 2-Amino-3-(hydroxymethyl)pyridine

A solution of 2.4M lithium aluminum hydride in THF (181 mL g, 434 mmol)was added portionwise to a suspension of 2-amino-3-carboxypyridine (30.0g, 217 mmol) in THF (350 mL) at 0° C. Once the addition was completed,the reaction mixture was stirred at room temperature for 15 minutes andthen at reflux overnight. The mixture was then cooled to 0° C. andhydrolyzed by the successive addition of water (18 mL), a 1M solution ofsodium hydroxide (18 mL) and water (50 mL). The resulting whitesuspension was stirred for one hour, filtered over Celite® and the cakewas washed with THF (400 mL). After concentration to dryness of thefiltrate, the title product was obtained as a light brown oil (25.1 g,87%, py 93.1%).

LCMS m/z 125.0 (M+H)⁺

Step 2: 2-Amino-5-bromo-3-(hydroxymethyl)pyridine

Bromine (10.4 mL, 202 mmol) was added dropwise over 1 hour to a solutionof 2-amino-3-(hydroxymethyl)pyridine (25.1 g, 202 mmol) in acetic acid(500 mL) at room temperature. After complete addition the reactionmixture was stirred for an extra hour. After concentration to dryness,the residue was partitioned between 1M Na2CO3 (750 mL) and ethyl acetate(500 mL). The aqueous layer was separated and extracted one more timewith ethyl acetate (500 mL). The combined organic phases were washedwith a saturated solution of sodium chloride (500 mL), dried over sodiumsulfate, filtered and concentrated to dryness. After trituration of theresidue in DCM/heptane and extra washing with DCM the title product wasobtained as a light yellow solid (30.0 g, 70%, py 97.3%).

LCMS m/z 203.0 (M+H)⁺

Step 3: 2-Amino-5-bromo-3-(bromomethyl)pyridine hydrobromide

A solution of 2-amino-5-bromo-3-(hydroxymethyl)pyridine (34.6 g, 170.0mmol) in hydrobromic acid (48% in H₂O, 93 mL) was stirred at refluxovernight. The reaction mixture was cooled to room temperature, theprecipitated product filtered and washed with H₂O (100 mL) and dried.The title product was obtained as a light yellow solid (36.1 g, 56%, py96.5%).

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 8.27 (dd, J=2 Hz and 6 Hz, 2H), 4.75(s, 2H).

Step 4: N-Boc ethylisonipecotate

Boc₂O (15.58 g, 71.4 mmol) and triethylamine (10.85 mL, 78 mmol) weresuccessively added to a solution of ethyl isonipecotate (10.2 g, 64.9mmol) in dichloromethane (50 mL) at room temperature. The reactionmixture was stirred overnight. The reaction mixture was diluted byaddition of a saturated solution of ammonium chloride (50 mL). Theaqueous layer was separated and extracted with dichloromethane (2×50mL). The combined organic phases were dried over sodium sulphate,filtered and concentrated to dryness. The title product was obtained asa colorless oil (16.1 g, 96%, py>95%).

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 4.14 (q, J=7 Hz, 2H), 4.02 (br, 2H),2.83 (m, 2H), 2.44 (m, 1H), 1.87 (m, 2H), 1.62 (m, 2H), 1.45 (s, 9H),1.25 (t, J=7 Hz, 3H).

Step 5: tert-Butyl6-bromo-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-1′-carboxylate

A solution of 1.8 M LDA in THF (1.6 mL, 2.88 mmol) was added dropwiseover 15 minutes to a cold (−78° C.) solution of5-bromo-3-(bromomethyl)pyridine-2-amine hydrobromide (1.0 g, 2.88 mmol)in dry THF (10 mL) under argon. The reaction mixture was stirred for anadditional 15 minutes. In a separate flask, a solution of 1.8 M LDA inTHF (4.81 mL, 8.65 mmol) was added dropwise over 30 minutes to a coldsolution of N-Boc ethylisonipecotate (2.23 g, 8.65 mmol) in dry THF (20ml). The reaction mixture was stirred for an additional 30 minutes. Thelithium salt of N-Boc ethylisonipecotate was then added via cannuladropwise over 30 minutes to the lithium salt of5-bromo-3-(bromomethyl)pyridine-2-amine. The mixture was stirred at −78°C. for 2 hours and allowed to warm to room temperature. The reactionmixture was quenched with a saturated solution of ammonium chloride (30mL) and ethyl acetate (30 mL) was added. The layers were separated andthe organic phase was washed with water (2×30 mL) and brine (50 mL),dried over sodium sulphate, filtered and concentrated to dryness. Theresidue was triturated with EtOAc. The title product was obtained as awhite solid (257 mg, 19%, py 85.7%).

LCMS m/z 394 (M−H)⁻

Step 6: (E)-tert-Butyl6-(3-tert-butoxy-3-oxoprop-1-enyl)-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-1′-carboxylate

Tert-Butyl acrylate (3.9 mL, 26.8 mmol), diisopropylethylamine (2.46 mL,14.1 mmol) and P(o-tolyl)₃ (409 mg, 1.34 mmol) were successively addedto a suspension of tert-butyl6-bromo-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-1′-carboxylate(2.66 g, 6.7 mmol) in propionitrile (107 mL) and dimethylformamide (40mL) in a sealed tube. The resulting mixture was then purged with argonprior to the addition of palladium acetate (151 mg, 0.673 mmol). Themixture was purged with argon again and refluxed overnight. The reactionmixture was then filtered on Celite® and the cake was washed with DCM(50 mL). The filtrate was concentrated to dryness and the residue wastriturated with dichloromethane. The title product was obtained as alight grey solid (1.83 g, 61%, py 79.9%).

LCMS m/z 442 (M−H)⁻

Step 7:(E)-3-(2-Oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-6-yl)acrylicacid hydrochloride

Trifluoroacetic acid (5.5 mL) was added to a suspension of(E)-3-(2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-6-yl)acrylicacid hydrochloride (540 mg, 1.21 mmol) in dichloromethane (5.5 mL). Thereaction mixture was stirred at room temperature for 1 hour andconcentrated to dryness. The resulting residue was suspended in asolution of hydrochloric acid, 4N in dioxane (11 ml). After 10 minutesstirring at room temperature, the precipitate was filtered andtriturated with diethyl ether. The title product was obtained as a whitesolid (455 mg, 109%, py 98.9%).

LCMS m/z 288 (M+H —HCl)⁺

Step 8:(E)-3-(1′-Methyl-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-6-yl)acrylicacid

Sodium triacetoxyborohydride (671 mg, 3.17 mmol) and paraformaldehyde(95 mg, 3.17 mmol) were successively added to a suspension of(E)-3-(2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-6-yl)acrylicacid (455 mg, 1.58 mmol) in 1,2-dichloroethane (40 mL) at roomtemperature. The reaction mixture was then heated to 70° C. and stirredfor 2 hours. The reaction mixture was cooled to room temperature, theprecipitated product filtered and washed with H₂O (50 mL) and MeOH (3×50mL) and dried. The title product was obtained as a white solid (319 mg,66%, py 74.1%).

LCMS m/z 302 (M+H)⁺

Example 16-[(1E)-3-Azetidin-1-yl-3-oxoprop-1-en-1-yl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E1)

A 16 mL vial flask was successively charged with(2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride (50 mg, 0.20 mmol), prepared (as in J. Med. Chem. 2003,46, 9, 1627-1635) from 6-bromo-3,4-dihydro-1,8-naphthyridin-2(1H)-onedescribed in U.S. Pat. No. 4,866,074 (Rorer Pharmaceutical Corp.), DMF(4.8 mL), HOBt (32 mg, 0.23 mmol), DIPEA (78 μL, 0.47 mmol), azetidine(16 μL, 0.23 mmol) and EDAC (45 mg, 0.23 mmol). The reaction mixture wasstirred at room temperature overnight and concentrated to dryness. Theresidue was purified twice on preparative TLC (eluent:dichloromethane/MeOH, 95/5) to give the title compound (31 mg, 62%) as awhite solid.

LCMS (ESI+) m/z 258 (M+H)⁺: 100%.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 10.65 (br s, 1H), 8.40-8.31 (m, 1H),8.06-7.98 (m, 1H), 7.37 (d, J=15.9 Hz, 1H), 6.68 (d, J=15.9 Hz, 1H),4.27 (t, J=7.5 Hz, 2H), 3.93 (t, J=7.5 Hz, 2H), 2.90 (t, J=7.2 Hz, 2H),2.23 (qt, J=7.5 Hz, 2H). The other CH₂ of the naphthyridinone moiety ishidden by DMSO signal.

Example 26-[(1E)-3-Oxo-3-pyrrolidin-1-ylprop-1-en-1-yl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E2)

A 16 mL vial flask was successively charged with(2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride (50 mg, 0.20 mmol), DMF (4.8 mL), HOBt (32 mg, 0.23 mmol),DIPEA (78 μL, 0.47 mmol), pyrrolidine (20 μL, 0.23 mmol) and EDAC (45mg, 0.23 mmol). The reaction mixture was stirred at room temperatureovernight and concentrated to dryness. The residue was diluted indichloromethane and washed with water. The organic layer wasconcentrated to dryness and the residue was purified on preparative TLC(eluent: dichloromethane/MeOH, 95/5) to give the title compound (33 mg,62%) as a white solid.

LCMS (ESI+) m/z 272 (M+H)⁺: 100%.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 10.64 (br s, 1H), 8.38-8.31 (m, 1H),8.07-8.01 (m, 1H), 7.42 (d, J=15.3 Hz, 1H), 6.96 (d, J=15.3 Hz, 1H),3.63 (t, J=6.8 Hz, 2H), 3.39 (t, J=6.8 Hz, 2H), 2.91 (t, J=7.2 Hz, 2H),1.91 (qt, J=6.8 Hz, 2H), 1.81 (qt, J=6.8 Hz, 2H). The other CH₂ of thenaphthyridinone moiety is hidden by DMSO signal.

Example 36-[(1E)-3-Oxo-3-piperidin-1-ylprop-1-en-1-yl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E3)

A 16 mL vial flask was successively charged with(2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride (50 mg, 0.20 mmol), DMF (4.8 mL), HOBt (32 mg, 0.23 mmol),DIPEA (78 μL, 0.47 mmol), piperidine (23 μL, 0.23 mmol) and EDAC (45 mg,0.23 mmol). The reaction mixture was stirred at room temperatureovernight and concentrated to dryness. The residue was diluted indichloromethane and washed with water. The organic layer wasconcentrated to dryness and the residue was purified on preparative TLC(eluent: dichloromethane/MeOH, 95/5) to give the title compound (39 mg,69%) as a white solid.

LCMS (ESI+) m/z 286 (M+H)⁺: 100%.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 10.64 (br s, 1H), 8.39-8.31 (m, 1H),8.12-8.07 (m, 1H), 7.42 (d, J=15.3 Hz, 1H), 7.24 (d, J=15.3 Hz, 1H),3.72-3.58 (m, 2H), 3.58-3.46 (m, 2H), 2.91 (t, J=6.9 Hz, 2H), 1.70-1.57(m, 2H), 1.57-1.42 (m, 4H). The other CH₂ of the naphthyridinone moietyis hidden by DMSO signal.

Example 46-{(1E)-3-[4-(2-Hydroxyethyl)piperidin-1-yl]-3-oxoprop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E4)

A 16 mL vial flask was successively charged with(2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride (50 mg, 0.20 mmol), DMF (4.8 mL), HOBt (32 mg, 0.23 mmol),DIPEA (78 μL, 0.47 mmol), 4-piperidineethanol (30 mg, 0.23 mmol) andEDAC (45 mg, 0.23 mmol). The reaction mixture was stirred at roomtemperature overnight and concentrated to dryness. The residue waspurified on column chromatography (eluent: dichloromethane/MeOH, 95/5)to give a white solid. This solid was triturated in MeOH, filtered,washed with MeOH and diethyl ether and dried to give the title compound(35 mg, 55%) as a white solid.

LCMS (ESI+) m/z 330 (M+H)⁺: 100%. Two peaks due to its protonationduring the analysis.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 10.64 (br s, 1H), 8.35-8.32 (m, 1H),8.11-8.07 (m, 1H), 7.42 (d, J=15.3 Hz, 1H), 7.24 (d, J=15.3 Hz, 1H),4.52-4.42 (m, 1H), 4.38 (t, J=5.1 Hz, 1H), 4.32-4.22 (m, 1H), 3.52-3.42(m, 2H), 3.11-2.96 (m, 1H), 2.91 (t, J=7.5 Hz, 2H), 2.69-2.57 (m, 1H),1.81-1.57 (m, 3H), 1.37 (q, J=6.6 Hz, 2H), 1.12-0.93 (m, 2H). The otherCH₂ is hidden by DMSO signal.

Example 56-[(1E)-3-{[4-(4-Fluorophenoxy)methyl]piperidin-1-yl}-3-oxoprop-1-en-1-yl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E5) Step 1: tert-Butyl4-[(4-fluorophenoxy)methyl]piperidine-1-carboxylate

4-Fluorophenol (0.52 g, 4.64 mmol) and triphenylphosphine (1.22 g, 4.64mmol) were added to a solution of N-boc-piperidine-4-methanol (500 mg,2.32 mmol) in anhydrous THF (12 mL) under nitrogen. The reaction mixturewas cooled to 0° C. and DEAD (670 μL, 3.69 mmol) was added dropwise. Thesolution was allowed to warm to room temperature and stirred overnight.The reaction mixture was concentrated under reduced pressure thendiluted with dichloromethane and filtered. The filtrate was washed threetimes with NaOH 0.2N, dried over Na₂SO₄ and concentrated. The residuewas purified on column chromatography (eluent: pentane/EtOAc 95/5) togive the title compound (538 mg, 75%) as a yellow oil.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 7.17-7.02 (m, 2H), 6.98-6.88 (m,2H), 4.02-3.88 (m, 2H), 3.79 (d, J=6.3 Hz, 2H), 2.83-2.60 (m, 2H),1.96-1.79 (m, 1H), 1.79-1.64 (m, 2H), 1.39 (s, 9H), 1.23-1.04 (m, 2H).

Step 2: 4-[(4-Fluorophenoxy)methyl]piperidine hydrochloride

To a cooled solution of tert-butyl4-[(4-fluorophenoxy)methyl]piperidine-1-carboxylate (538 mg, 1.74 mmol;which may be prepared as described in Step 1) in dichloromethane (11.5mL) was added dropwise HCl 4N in dioxane (8.5 mL). The solution waswarmed to room temperature and stirred for 1 h. The solvent wasevaporated under reduced pressure to give the title compound (416 mg,97%) as a white solid.

¹H NMR (DMSO-d₆, 300 MHz): δ(ppm): 9.12-8.88 (m, 1H), 8.80-8.56 (m, 1H),7.17-7.02 (m, 2H), 7.01-6.86 (m, 2H), 3.82 (d, J=6.6 Hz, 2H), 3.32-3.21(m, 2H), 2.97-2.78 (m, 2H), 2.10-1.95 (m, 1H), 1.94-1.81 (m, 2H),1.58-1.37 (m, 2H).

Step 3:6-[(1E)-3-{[4-(4-Fluorophenoxy)methyl]piperidin-1-yl}-3-oxoprop-1-en-1-yl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one

A 16 mL vial flask was successively charged with(2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride (30 mg, 0.12 mmol), DMF (3 mL),4-[(4-fluorophenoxy)methyl]piperidine hydrochloride (34 mg, 0.14 mmol;which may be prepared as described in Step 2), DIPEA (48 μL, 0.28 mmol)and EDAC (27 mg, 0.14 mmol). The reaction mixture was stirred at roomtemperature overnight and concentrated to dryness. The residue waspurified on preparative TLC (eluent: dichloromethane/NH₃ 7N in MeOH,2.5%) to give a pale yellow solid. This solid was triturated in acetone,filtered, washed with acetone and diethyl ether then dried to give thetitle compound (22 mg, 45%) as a white solid.

LCMS (ESI+) m/z 410 (M+H)⁺: 100%.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 10.64 (br s, 1H), 8.40-8.25 (m, 1H),8.16-8.04 (m, 1H), 7.44 (d, J=15.3 Hz, 1H), 7.26 (d, J=15.3 Hz, 1H),7.18-7.05 (m, 2H), 7.02-6.85 (m, 2H), 4.60-4.25 (m, 2H), 3.90-3.73 (m,2H), 3.16-3.01 (m, 1H), 2.98-2.80 (m, 2H), 2.77-2.60 (m, 1H), 2.13-1.93(m, 1H), 1.91-1.70 (m, 2H), 1.34-1.05 (m, 2H). The CH₂ missing is hiddenby DMSO signal.

Example 66-[(1E)-3-Oxo-3-(3-phenoxyazetidin-1-yl)prop-1-en-1-yl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E6) Step 1: 1-(Diphenylmethyl)azetidin-3-yl methanesulfonate

A 100 mL flask was charged with 1-diphenylmethylazetidin-3-ol (1.5 g,6.27 mmol) and pyridine (15 mL). The solution was cooled to −20° C. andmethane sulfonyl chloride (0.73 mL, 9.4 mmol) was added dropwise. Thereaction mixture was stirred at −20° C. for 1 h and then left 3 days at4° C. The solution was poured on ice and the resulting precipitate wasfiltered, washed 3 times with H₂O and 3 times with pentane. The solidwas dried under reduced pressure to give the title compound (1.92 g,96%) as a white solid.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 7.44-7.03 (m, 10H), 5.16-4.96 (m,1H), 4.59-4.42 (m, 1H), 3.61-3.21 (m, 4H), 3.18 (s, 3H).

Step 2: 1-(Diphenylmethyl)-3-phenoxyazetidine

To a cooled solution of phenol (149 mg, 1.58 mmol) in DMF (3.9 mL), NaH(60% in oil, 95 mg, 2.37 mmol) was added portionwise and the suspensionwas stirred at 0° C. for 15 min. 1-(Diphenylmethyl)azetidin-3-ylmethanesulfonate (500 mg, 1.58 mmol; which may be prepared as describedin Step 1) was then added and the reaction mixture stirred at 80° C.overnight and concentrated under reduced pressure. The residue waspurified on column chromatography (eluent: pentane/EtOAc 98/2 to 95/5)to give the title compound (332 mg, 67%) as a light yellow solid.

¹H NMR (DMSO-d6, 300 MHz): δ (ppm): 7.49-7.34 (m, 3H), 7.32-7.07 (m,9H), 6.96-6.87 (m, 1H), 6.85-6.72 (m, 2H), 4.88-4.75 (m, 1H), 4.51 (brs, 1H), 3.66-3.58 (m, 2H), 3.00-2.92 (m, 2H).

Step 3: 3-Phenoxyazetidine hydrochloride

A 50 mL flask was charged with 1-(diphenylmethyl)-3-phenoxyazetidine(328 mg, 1.04 mmol; which may be prepared as described in Step 2) and1,2-dichloroethane (4.6 mL). 1-Chloroethyl chloroformate (164 μL, 1.35mmol) was added and the reaction mixture was stirred at 70° C. for 1.5h. After cooling to room temperature, MeOH (4.6 mL) was added and thereaction mixture was stirred at 70° C. for 1.5 h. The reaction mixturewas concentrated to dryness. The crude product was triturated in pentaneto give the title compound (204 mg, quantitative) as pale yellowcrystals. This product was used in the next step without furtherpurification.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 9.70-9.38 (m, 2H), 7.29-7.18 (m,2H), 7.08-6.93 (m, 1H), 6.90-6.78 (m, 2H), 5.13-4.98 (m, 1H), 4.51-4.29(m, 2H), 4.04-3.80 (m, 2H).

Step 4:6-[(1E)-3-Oxo-3-(3-phenoxyazetidin-1-yl)prop-1-en-1-yl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one

A 16 mL vial flask was successively charged with(2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride (30 mg, 0.12 mmol), DMF (3 mL), 3-phenoxyazetidinehydrochloride (26 mg, 0.14 mmol; which may be prepared as described inStep 3), DIPEA (48 μL, 0.28 mmol) and EDAC (27 mg, 0.14 mmol). Thereaction mixture was stirred at room temperature overnight andconcentrated to dryness. The residue was purified on preparative TLC(eluent: dichloromethane/NH₃ 7N in MeOH, 2.5%) to give a pale yellowsolid. This solid was triturated in acetone, filtered, washed withacetone and diethyl ether then dried to give the title compound (15 mg,36%) as a white solid.

LCMS (ESI+) m/z 350 (M+H)⁺: 100%.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 10.66 (br s, 1H), 8.37-8.29 (m, 1H),8.05-7.98 (m, 1H), 7.42 (d, J=15.8 Hz, 1H), 7.37-7.25 (m, 2H), 7.04-6.94(m, 1H), 6.91-6.82 (m, 2H), 6.76 (d, J=15.8 Hz, 1H), 5.14-5.03 (m, 1H),4.79-4.67 (m, 1H), 4.47-4.37 (m, 1H), 4.26-4.15 (m, 1H), 3.95-3.84 (m,1H), 2.95-2.80 (m, 2H).

The CH₂ missing is hidden by the DMSO signal.

Example 76-[(1E)-3-Oxo-3-(2-phenylpyrrolidin-1-yl)prop-1-en-1-yl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E7)

A 16 mL vial flask was successively charged with(2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride (30 mg, 0.12 mmol), DMF (3 mL), 2-phenylpyrrolidine (21mg, 0.14 mmol), DIPEA (48 μL, 0.28 mmol) and EDAC (27 mg, 0.14 mmol).The reaction mixture was stirred at room temperature and concentrated todryness. LC/MS showed the presence of the target compound and nostarting material after 24 h. The residue was purified on preparativeTLC (eluent: dichloromethane/NH₃ 7N in MeOH, 2.5%) to give a pale yellowsolid. This solid as triturated in acetone, filtered, washed withacetone and dried to give the title compound (7 mg, 17%) as a whitesolid.

LCMS (ESI+) m/z 348 (M+H)⁺: 100%.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 10.73-10.49 (m, 1H), 8.41-8.35 (m,0.5H), 8.19-8.05 (m, 1H), 7.66-7.56 (m, 0.5H), 7.48-7.00 (m, 6.5H), 6.58(d, J=15.3 Hz, 0.5H), 5.46-5.09 (m, 1H), 4.05-3.55 (m, 2H), 2.99-2.77(m, 2H), 2.01-1.61 (m, 4H). The other CH₂ is hidden by DMSO signal.

Example 86-[(1E)-3-Oxo-3-(4-propylpiperidin-1-yl)prop-1-en-1-yl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E8)

A 16 mL vial flask was successively charged with(2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride (30 mg, 0.12 mmol), DMF (3 mL), 4-N-propylpiperidine (18mg, 0.14 mmol), DIPEA (48 μL, 0.28 mmol) and EDAC (27 mg, 0.14 mmol).The reaction mixture was stirred at room temperature overnight andconcentrated to dryness. LC/MS showed the presence of the targetcompound and no starting material after 24 h. The residue was purifiedon preparative TLC (eluent: dichloromethane/NH₃ 7N in MeOH, 2.5%) togive a white solid. This solid was triturated in acetone, filtered,washed with acetone and diethyl ether to give the title compound (15 mg,38%) as a white solid.

LCMS (ESI+) m/z 328 (M+H)⁺: 100%.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 10.64 (br s, 1H), 8.40-8.27 (m, 1H),8.14-8.02 (m, 1H), 7.42 (d, J=15.3 Hz, 1H), 7.23 (d, J=15.3 Hz, 1H),4.55-4.15 (m, 2H), 3.10-2.97 (m, 1H), 2.96-2.81 (m, 2H), 1.80-1.62 (m,2H), 1.60-1.40 (m, 1H), 1.39-1.11 (m, 4H), 1.07-0.91 (m, 1H), 0.87 (t,J=7.2 Hz, 3H). The 2 CH₂ missing are hidden by the DMSO signal.

Example 96-[(1E)-3-{[3-(4-Fluorophenoxy)methyl]piperidin-1-yl}-3-oxoprop-1-en-1-yl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E9) Step 1: tert-Butyl3-[(4-fluorophenoxy)methyl]piperidine-1-carboxylate

4-Fluorophenol (520 mg, 4.64 mmol) and triphenylphosphine (1.22 g, 4.64mmol) were added to a solution of N-boc-piperidine-3-methanol (500 mg,2.32 mmol) in anhydrous THF (12 mL) under nitrogen. The reaction mixturewas cooled to 0° C. and DEAD (673 μL, 3.71 mmol) was added dropwise. Thesolution was allowed to warm to room temperature and stirred overnight.The reaction mixture was concentrated under reduced pressure thendiluted with dichloromethane and filtered. The filtrate was washed threetimes with NaOH 0.2N, dried over Na₂SO₄ and concentrated. The residuewas purified on column chromatography (eluent: pentane/EtOAc 95/5) togive the title compound (300 mg, 42%) as a yellow oil.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 7.18-7.03 (m, 2H), 7.01-6.87 (m,2H), 4.09-3.55 (m, 4H), 3.02-2.76 (m, 1H), 1.95-1.52 (m, 3H), 1.49-1.19(m, 12H).

Step 2: 3-[(4-Fluorophenoxy)methyl]piperidine hydrochloride

To a cooled solution of tert-butyl3-[(4-fluorophenoxy)methyl]piperidine-1-carboxylate (300 mg, 1.03 mmol;which may be prepared as described in Step 1) in dichloromethane (6.8mL) was added dropwise HCl 4N in dioxane (5.0 mL). The solution waswarmed to room temperature and stirred for 1 h. The solvent wasevaporated under reduced pressure to give the title compound (267 mg,quantitative) as a white solid.

The product was used in the next step without further analysis.

Step 3:6-[(1E)-3-{[3-(4-Fluorophenoxy)methyl]piperidin-1-yl}-3-oxoprop-1-en-1-yl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one

A 16 mL vial flask was successively charged with(2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride (30 mg, 0.12 mmol), DMF (3 mL),3-[(4-fluorophenoxy)methyl]piperidine hydrochloride (35 mg, 0.14 mmol;which may be prepared as described in Step 2), DIPEA (48 μL, 0.28 mmol)and EDAC (27 mg, 0.14 mmol). The reaction mixture was stirred at roomtemperature overnight and concentrated to dryness. The residue waspurified on preparative TLC (eluent: dichloromethane/NH₃ 7N in MeOH,2.5%) to give a pale yellow solid. This solid was triturated inmethanol, filtered, washed with methanol and diethyl ether then dried togive the title compound (23 mg, 47%) as a white solid.

LCMS (ESI+) m/z 410 (M+H)⁺: 100%.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 10.64 (br s, 1H), 8.38-8.22 (m, 1H),8.15-7.87 (m, 1H), 7.53-6.84 (m, 6H), 4.60-3.95 (m, 2H), 3.95-3.73 (m,2H), 3.20-2.98 (m, 1H), 2.98-2.78 (m, 2H), 2.77-2.58 (m, 1H), 2.00-1.58(m, 3H), 1.56-1.26 (m, 2H). The CH₂ missing is hidden by the DMSOsignal.

Example 106-[(1E)-3-Oxo-3-(3-phenoxypyrrolidin-1-yl)prop-1-en-1-yl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E10) Step 1: tert-Butyl 3-hydroxypyrrolidine-1-carboxylate

To a solution of 3-pyrrolidinol (1.82 g, 20.87 mmol) and triethylamine(6.4 mL, 45.92 mmol) in dichloromethane (104 mL) was addeddi-tert-butyldicarbonate (5.01 g, 22.96 mmol) in portions at 5° C. Afterstirring at room temperature for 16 h the reaction mixture was washedwith HCl 0.1N, saturated NaHCO₃ solution and brine then dried overNa₂SO₄. The combined organic layers were concentrated under reducedpressure to give the title compound (3.78 g, 97%) as a dark orange oil.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 4.95-4.84 (m, 1H), 4.30-4.13 (m,1H), 3.35-3.01 (m, 4H), 1.92-1.64 (m, 2H), 1.39 (s, 9H).

Step 2: tert-Butyl 3-phenoxypyrrolidine-1-carboxylate

Phenol (503 mg, 5.34 mmol) and triphenylphosphine (1.40 g, 5.34 mmol)were added to a solution of tert-butyl3-hydroxypyrrolidine-1-carboxylate (500 mg, 2.67 mmol; which may beprepared as described in Step 1) in anhydrous THF (13 mL) undernitrogen. The reaction mixture was cooled to 0° C. and DEAD (775 μL,4.27 mmol) was added dropwise. The solution was allowed to warm to roomtemperature and stirred overnight. The reaction mixture was concentratedunder reduced pressure then diluted with dichloromethane and filtered.The filtrate was washed three times with NaOH 0.2N and brine, dried overNa₂SO₄ then concentrated. The residue was purified on columnchromatography (eluent: pentane EtOAc 9/1) to give the title compound(175 mg, 25%) as a yellow oil.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 7.37-7.21 (m, 2H), 7.03-6.85 (m,3H), 5.08-4.92 (m, 1H), 3.60-3.32 (m, 4H), 2.19-1.93 (m, 2H), 1.47-1.27(m, 9H).

Step 3: 3-Phenoxypyrrolidine hydrochloride

To a cooled solution of tert-butyl 3-phenoxypyrrolidine-1-carboxylate(172 mg, 0.65 mmol; which may be prepared as described in Step 2) indichloromethane (4.3 mL) was added dropwise HCl 4N in dioxane (3.2 mL).The solution was warmed to room temperature and stirred for 1 h. Thesolvent was evaporated under reduced pressure to give the title compound(135 mg, quantitative) as an orange oil.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 9.77-9.58 (m, 1H), 9.57-9.38 (m,1H), 7.37-7.26 (m, 2H), 7.03-6.90 (m, 3H), 5.18-5.09 (m, 1H), 3.59-3.07(m, 4H), 2.27-2.03 (m, 2H).

Step 4:6-[(1E)-3-Oxo-3-(3-phenoxypyrrolidin-1-yl)prop-1-en-1-yl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one

A 16 mL vial flask was successively charged with(2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride (30 mg, 0.12 mmol), DMF (3 mL), 3-phenoxypyrrolidinehydrochloride (28 mg, 0.14 mmol; which may be prepared as described inStep 3), DIPEA (48 μL, 0.28 mmol) and EDAC (27 mg, 0.14 mmol). Thereaction mixture was stirred at room temperature overnight andconcentrated to dryness. The residue was purified on preparative TLC(eluent: dichloromethane/NH₃ 7N in MeOH, 2.5%) to give a pale yellowsolid. This solid was triturated in methanol, filtered, washed withmethanol, acetone and diethyl ether then dried to give the titlecompound (30 mg, 68%) as a white solid.

LCMS (ESI+) m/z 364 (M+H)⁺: 100%.

¹H NMR (DMSO-_(d6), 300 MHz): δ (ppm): 10.74-10.61 (m, 1H), 8.42-8.29(m, 1H), 8.14-8.00 (m, 1H), 7.46 (d, J=15.6 Hz, 1H), 7.37-7.21 (m, 2H),7.11-6.81 (m, 4H), 5.22-5.02 (m, 1H), 4.03-3.47 (m, 4H), 3.00-2.78 (m,2H), 2.37-1.99 (m, 2H). The CH₂ missing is hidden by the DMSO signal.

Example 116-{(1E)-3-[3-(5-Methyl-1,2,4-oxadiazol-3-yl)azetidin-1-yl]-3-oxoprop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E11) Step 1: Azetidine-3-carbonitrile hydrochloride

A 50 mL flask was charged with 1-benzhydrylazetane-3-carbonitrile (500mg, 2.01 mmol) and 1,2-dichloroethane (8.9 mL). 1-chloroethylchloroformate (285 μL, 2.61 mmol) was added and the reaction mixture wasstirred at 70° C. for 1.5 h. After cooling to room temperature, methanol(8.9 mL) was added and the reaction mixture was stirred at 70° C. for1.5 h. The reaction mixture was concentrated to dryness. The crudemixture was triturated in pentane to give a dark solid (250 mg,quantitative) which was used without further purification.

Step 2: tert-Butyl 3-cyanoazetidine-1-carboxylate

To a solution of azetidine-3-carbonitrile hydrochloride (250 mg, 2.01mmol theoretical; which may be prepared as described in Step 1) andtriethylamine (1.12 mL, 8.04 mmol) in dichloromethane (10.2 mL) wasadded di-tert-butyldicarbonate (482 mg, 2.21 mmol) portionwise at 5° C.After stirring at room temperature for 16 h, the reaction mixture waswashed with HCl 0.5N and brine then dried over Na₂SO₄. The solvent wasremoved under reduced pressure and the crude mixture purified on columnchromatography (eluent: Pentane/EtOAc 95/5 to 4/1) to give the compound(190 mg, 52%) as a clear oil.

¹H NMR (CDCl₃, 300 MHz): δ (ppm): 4.29-4.05 (m, 4H), 3.48-3.29 (m, 1H),1.44 (s, 9H).

Step 3: tert-Butyl3-[(Z)-amino(hydroxyimino)methyl]azetidine-1-carboxylate

In a 16 mL vial, tert-butyl 3-cyanoazetidine-1-carboxylate (190 mg, 1.04mmol; which may be prepared as described in Step 2) was dissolved inethanol (2.9 mL), then hydroxylamine hydrochloride (101 mg, 1.46 mmol)and triethylamine (247 μL, 1.77 mmol) were added. The reaction mixturewas stirred at reflux for 3 h, cooled and concentrated. The residue wastaken up in EtOAc and water, the aqueous layer extracted with EtOAc,dried over Na₂SO₄ and concentrated to give the product as a white solid(170 mg, 76%).

¹H NMR (DMSO-d₆, 300 MHz) δ (ppm): 9.10 (s, 1H), 5.54-5.43 (br s, 2H),4.00-3.78 (m, 4H), 3.23-3.08 (m, 1H), 1.37 (s, 9H).

Step 4: tert-Butyl3-(5-methyl-1,2,4-oxadiazol-3-yl)azetidine-1-carboxylate

In a 16 mL vial, tert-butyl3-[(Z)-amino(hydroxyimino)methyl]azetidine-1-carboxylate (170 mg, 0.74mmol; which may be prepared as described in Step 3) was dissolved inacetonitrile (7.4 mL) and cooled to 0° C. under nitrogen. DIPEA (387 μL,2.22 mmol) and acetyl chloride (105 μL, 1.48 mmol) were added dropwiseand the reaction mixture was allowed to warm to room temperature thenheated to 80° C. overnight, cooled and concentrated. The residue wastaken up in EtOAc and water, the aqueous layer extracted with EtOAc,dried over Na₂SO₄ and concentrated. The residue was taken up in o-xylene(8.4 mL) and heated to 150° C. for 2 h and concentrated. The crudemixture was purified on column chromatography (eluent: Pentane/EtOAc7/3) to give the title compound (97 mg, 55%) as an oil.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 4.30-4.13 (m, 2H), 4.03-3.84 (m,3H), 2.59 (s, 3H), 1.39 (s, 9H).

Step 5: 3-Azetidin-3-yl-5-methyl-1,2,4-oxadiazole hydrochloride

To a cooled solution of tert-butyl3-(5-methyl-1,2,4-oxadiazol-3-yl)azetidine-1-carboxylate (97 mg, 0.41mmol; which may be prepared as described in Step 4) in dichloromethanewas added dropwise HCl 4N in dioxane (2.0 mL). The solution was warmedto room temperature and stirred for 1 h. The solvent was evaporatedunder reduced pressure to give the title compound (101 mg, quantitative)as a white solid. The product was used in the next step without furtheranalysis.

Step 6:6-{(1E)-3-[3-(5-Methyl-1,2,4-oxadiazol-3-yl)azetidin-1-yl]-3-oxoprop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one

A 16 mL vial flask was successively charged with(2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride (30 mg, 0.12 mmol), DMF (3 mL),3-azetidin-3-yl-5-methyl-1,2,4-oxadiazole hydrochloride (25 mg, 0.14mmol; which may be prepared as described in Step 5), DIPEA (48 μL, 0.28mmol) and EDAC (27 mg, 0.14 mmol). The reaction mixture was stirred atroom temperature overnight and concentrated to dryness. The residue waspurified on preparative TLC (eluent: dichloromethane/NH₃ 7N in MeOH,2.5%) to give a white solid. This solid was triturated in acetone anddiethyl ether, filtered, washed with acetone and diethyl ether thendried to give the title compound (23 mg, 56%) as a white solid.

LCMS (ESI+) m/z 340 (M+H)⁺: 100%.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 10.67 (br s, 1H), 8.41-8.30 (m, 1H),8.07-7.98 (m, 1H), 7.43 (d, J=15.8 Hz, 1H), 6.75 (d, J=15.8 Hz, 1H),4.75-4.62 (m, 1H), 4.48-4.25 (m, 2H), 4.16-3.95 (m, 2H), 2.96-2.81 (m,2H), 2.60 (s, 3H). The CH₂ missing is hidden by the DMSO signal.

Example 126-{(1E)-3-Oxo-3-[3-(2-thienylmethoxy)azetidin-1-yl]prop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E12) Step 1: 2-(Chloromethyl)thiophene

In a 15 mL flask, thiophene-2-methanol (332 μL, 3.50 mmol) was dissolvedin tetrahydrofuran (2 mL) and cooled at 0° C. under nitrogen. Thionylchloride (305 μL, 4.20 mmol) was added dropwise and the reaction mixturewas allowed to warm to room temperature and heated at 50° C. for 2 h.The crude mixture was concentrated under reduced pressure to give a darkoil (480 mg, quantitative). The product was used in the next stepwithout further purification.

¹H NMR (CDCl₃, 300 MHz): δ (ppm): 7.36-7.30 (m, 1H), 7.11-7.04 (m, 1H),6.99-6.93 (m, 1H), 4.82 (s, 2H).

Step 2: 1-(Diphenylmethyl)-3-(2-thienylmethoxy)azetidine

To a solution of 1-diphenylmethylazetidin-3-ol (359 mg, 1.5 mmol) in DMF(1 mL) at 0° C. under nitrogen was added NaH (60% in oil, 66 mg, 1.65mmol). The suspension was stirred for 0.5 h at 0° C. then treated with2-(chloromethyl)thiophene (464 mg, 3.5 mmol; which may be prepared asdescribed in Step 1) dissolved in DMF (2 mL).

The mixture was allowed to warm to room temperature then heated at 80°C. overnight. The reaction mixture was cooled, acetic acid (2 drops) wasadded and the mixture concentrated under reduced pressure. The crudematerial was purified on column chromatography (eluent: Pentane/EtOAc,9/1 to 7/3) to give the product (204 mg, 41%) as an orange oil.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 7.50-7.46 (m, 1H), 7.43-7.36 (m,4H), 7.29-7.21 (m, 4H), 7.20-7.12 (m, 2H), 7.06-7.02 (m, 1H), 6.99-6.94(m, 1H), 4.62-4.48 (m, 2H), 4.39 (br s, 1H), 4.23-4.12 (m, 1H),3.36-3.27 (m, 2H), 2.80-2.70 (m, 2H).

Step 3: 3-(2-Thienylmethoxy)azetidine hydrochloride

A 50 mL flask was charged with1-(diphenylmethyl)-3-(2-thienylmethoxy)azetidine (204 mg, 0.61 mmol;which may be prepared as described in Step 2) and 1,2-dichloroethane(2.7 mL). 1-Chloroethyl chloroformate (86 μL, 0.79 mmol) was added andthe reaction mixture was stirred at 70° C. for 1.5 h. After cooling toroom temperature, methanol (2.7 mL) was added and the reaction mixturewas stirred at 70° C. for 1.5 h. The reaction mixture was concentratedto dryness. The crude mixture was triturated in pentane to give a darkwax (140 mg, quantitative) which was used without further purification.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 9.21-8.85 (m, 2H), 7.62-7.52 (m,1H), 7.16-7.08 (m, 1H), 7.04-6.97 (m, 1H), 4.67 (s, 2H), 4.51-4.39 (m,1H), 4.13-3.96 (m, 2H), 3.84-3.68 (m, 2H).

Step 4:6-{(1E)-3-Oxo-3-[3-(2-thienylmethoxy)azetidin-1-yl]prop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one

A 16 mL vial flask was successively charged with(2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride (30 mg, 0.12 mmol), DMF (3 mL),3-(2-thienylmethoxy)azetidine hydrochloride (29 mg, 0.14 mmol; which maybe prepared as described in Step 3), DIPEA (48 μL, 0.28 mmol) and EDAC(27 mg, 0.14 mmol). The reaction mixture was stirred at room temperatureovernight and concentrated to dryness. The residue was purified onpreparative TLC (eluent: dichloromethane/NH₃ 7N in MeOH, 2.5%) to give abrown solid. This solid was triturated in acetone and diethyl ether,filtered, washed with diethyl ether then dried to give the titlecompound (8 mg, 18%) as a pale brown solid.

LCMS (ESI+) m/z 370 (M+H)⁺: 100%.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 10.66 (br s, 1H), 8.39-8.30 (m, 1H),8.04-7.98 (m, 1H), 7.58-7.51 (m, 1H), 7.39 (d, J=15.6 Hz, 1H), 7.15-7.07(m, 1H), 7.04-6.98 (m, 1H), 6.70 (d, J=15.6 Hz, 1H), 4.67 (s, 2H),4.51-4.39 (m, 2H), 4.18-4.05 (m, 2H), 3.77-3.68 (m, 1H), 2.95-2.85 (m,2H). The CH₂ missing is hidden by the DMSO signal.

Example 136-{(1E)-3-[2-(5-Methyl-1,2,4-oxadiazol-3-yl)piperidin-1-yl]-3-oxoprop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E13) Step 1: tert-Butyl2-[(Z)-amino(hydroxyimino)methyl]piperidine-1-carboxylate

In a 16 mL vial, N-boc-2-cyanopiperidine (500 mg, 2.38 mmol) wasdissolved in ethanol (6.7 mL), then hydroxylamine hydrochloride (231 mg,3.33 mmol) and triethylamine (0.56 mL, 4.05 mmol) were added. Thereaction mixture was stirred at reflux for 5 h, cooled and concentrated.The residue was taken up in EtOAc and water. The two layers wereseparated and the aqueous phase extracted with EtOAc. The combinedorganics were dried on Na₂SO₄ and concentrated to give the product as awhite solid (550 mg, 95%).

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 9.16 (s, 1H), 5.19 (br s, 2H),4.71-4.57 (m, 1H), 3.87-3.70 (m, 1H), 3.07-2.89 (m, 1H), 2.11-1.89 (m,1H), 1.62-1.36 (m, 5H), 1.38 (s, 9H).

Step 2: tert-Butyl2-(5-methyl-1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate

In a 16 mL vial, tert-butyl2-[(Z)-amino(hydroxyimino)methyl]piperidine-1-carboxylate (150 mg, 0.62mmol; which may be prepared as described in Step 1) was dissolved inacetonitrile (6.2 mL) and cooled at 0° C. under nitrogen. DIPEA (324 μL,1.86 mmol) and acetyl chloride (88 μL, 1.24 mmol) were added dropwiseand the reaction mixture was allowed to warm to room temperature thenheated to 100° C. for 4 h, cooled and concentrated. The residue wastaken up in EtOAc and water. The two layers were separated and theaqueous phase extracted with EtOAc. The combined organics were dried onNa₂SO₄ and concentrated. The residue was taken up in o-xylene (7 mL) andheated to 150° C. for 3 h then concentrated. The crude mixture waspurified on column chromatography (eluent: Pentane/EtOAc 7/3) to givethe product (55 mg, 33%) as a yellow oil.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 5.38-5.26 (m, 1H), 3.95-3.81 (m,1H), 2.99-2.76 (m, 1H), 2.57 (s, 3H), 2.17-2.05 (m, 1H), 1.87-1.68 (m,1H), 1.66-1.52 (m, 2H), 1.45-1.20 (m, 11H).

Step 3: 2-(5-Methyl-1,2,4-oxadiazol-3-yl)piperidine hydrochloride

To a cooled solution of tert-butyl2-(5-methyl-1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate (55 mg, 0.21mmol; which may be prepared as described in Step 2) in dichloromethane(1.7 mL) was added dropwise HCl 4N in dioxane (1.3 mL). The solution waswarmed to room temperature and stirred for 2 h. The solvent wasevaporated under reduced pressure to give the title compound (47 mg,quantitative) as a white powder.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 9.58-9.09 (m, 2H), 4.73-4.52 (m,1H), 3.17-2.94 (m, 2H), 2.68 (s, 3H), 2.20-2.04 (m, 1H), 1.88-1.51 (m,5H).

Step 4:6-{(1E)-3-[2-(5-Methyl-1,2,4-oxadiazol-3-yl)piperidin-1-yl]-3-oxoprop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one

A 16 mL vial flask was successively charged with(2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride (30 mg, 0.12 mmol), DMF (3 mL),2-(5-methyl-1,2,4-oxadiazol-3-yl)piperidine hydrochloride (29 mg, 0.14mmol; which may be prepared as described in Step 3), DIPEA (48 μL, 0.28mmol) and EDAC (27 mg, 0.14 mmol). The reaction mixture was stirred atroom temperature overnight and concentrated to dryness. The residue waspurified on preparative TLC (eluent: dichloromethane/NH₃ 7N in MeOH,2.5%) to give an oil. This oil was taken up in acetone, diethyl etherand concentrated. The resulting wax was finally dissolved indichloromethane, concentrated and dried to give the title compound (15mg, 34%) as a yellow solid.

LCMS (ESI+) m/z 368 (M+H)⁺: 100%.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 10.65 (br s, 1H), 8.44-8.29 (m, 1H),8.17-8.02 (m, 1H), 7.49 (d, J=15.3 Hz, 1H), 7.31 (d, J=15.3 Hz, 1H),5.97-5.77 (m, 1H), 4.57-4.23 (m, 1H), 3.26-3.04 (m, 1H), 2.98-2.78 (m,2H), 2.58 (s, 3H), 2.37-2.12 (m, 1H), 1.97-1.09 (m, 5H). The CH₂ missingis hidden by the DMSO signal.

Example 146-{(1E)-3-[4-Hydroxy-4-phenylpiperidin-1-yl]-3-oxoprop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E14)

A 16 mL vial flask was successively charged with(2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride (30 mg, 0.12 mmol), DMF (3 mL),4-hydroxy-4-phenylpiperidine (25 mg, 0.14 mmol), DIPEA (48 μL, 0.28mmol) and EDAC (27 mg, 0.14 mmol). The reaction mixture was stirred atroom temperature overnight and concentrated to dryness. The residue waspurified on preparative TLC (eluent: dichloromethane/MeOH, 95/5) to givea white solid. This solid was triturated in acetone and diethyl ether,filtered, washed with diethyl ether and then dried to give the titlecompound (18.5 mg, 41%) as a white solid.

LCMS (ESI+) m/z 378 (M+H)⁺: 100%.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 10.64 (br s, 1H), 8.39-8.30 (m, 1H),8.14-8.06 (m, 1H), 7.57-7.45 (m, 3H), 7.40-7.16 (m, 4H), 5.17 (s, 1H),4.52-4.11 (m, 2H), 3.57-3.39 (m, 1H), 3.16-2.99 (m, 1H), 2.97-2.82 (m,2H), 1.98-1.56 (m, 4H). The CH₂ missing is hidden by the DMSO signal.

Example 156-{(1E)-3-Oxo-3-[3-(pentyloxy)azetidin-1-yl]prop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E15) Step 1: 1-(Diphenylmethyl)-3-(pentyloxy)azetidine

A solution of 1-diphenylmethylazetidin-3-ol (300 mg, 1.25 mmol) in THF(4.5 mL) was cooled to 0° C. t-BuOK (1M in THF, 3.75 mL) was addeddropwise and the reaction mixture was stirred at room temperature for 1h then cooled to 0° C. 1-Iodopentane (816 μL, 6.25 mmol) was added andthe solution was stirred at room temperature for 18 h. The reactionmixture was diluted with H₂O and extracted twice with EtOAc. The organiclayers were combined, dried over Na₂SO₄ and concentrated to dryness. Theresidue was purified on column chromatography (eluent: pentane/EtOAc,95/5) to give the title compound (267 mg, 69%) as a clear oil.

LCMS (ESI+) m/z 310 (M+H)⁺: 100%.

Step 2: 1-(Diphenylmethyl)-3-(pentyloxy)azetidine

A 25 mL flask was charged with 1-(diphenylmethyl)-3-(pentyloxy)azetidine(267 mg, 0.86 mmol; which may be prepared as described in Step 1) and1,2-dichloroethane (3.8 mL). 1-Chloroethyl chloroformate (123 μL, 1.13mmol) was added and the reaction mixture was stirred at 70° C. for 1.5h. After cooling to room temperature, methanol (3.8 mL) was added andthe reaction mixture was stirred at 70° C. for 1.5 h. The reactionmixture was concentrated to dryness. The crude mixture was triturated inpentane to give a clear oil (145 mg, 94%) which was used without furtherpurification.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 9.29-8.80 (m, 2H), 4.38-4.24 (m,1H), 4.19-4.01 (m, 2H), 3.84-3.68 (m, 2H), 3.40-3.27 (m, 2H), 1.57-1.39(m, 2H), 1.37-1.18 (m, 4H), 0.87 (t, J=6.8 Hz, 3H).

Step 3:6-{(1E)-3-Oxo-3-[3-(pentyloxy)azetidin-1-yl]prop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one

A 16 mL vial flask was successively charged with(2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride (40 mg, 0.16 mmol), DMF (3.8 mL),1-(diphenylmethyl)-3-(pentyloxy)azetidine (34 mg, 0.19 mmol; which maybe prepared as described in Step 2), DIPEA (63 μL, 0.38 mmol) and EDAC(36 mg, 0.19 mmol). The reaction mixture was stirred at room temperaturefor 48 h and concentrated to dryness. The residue was purified onpreparative TLC (eluent: dichloromethane/MeOH, 9/1) to give a beigesolid. This solid was triturated in acetone to give the title compound(5 mg, 9%) as a white solid.

LCMS (ESI+) m/z 344 (M+H)⁺: 85%.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 10.67 (br s, 1H), 8.37-8.28 (m, 1H),8.03-7.93 (m, 1H), 7.40 (d, J=15.6 Hz, 1H), 6.70 (d, J=15.6 Hz, 1H),4.52-4.39 (m, 1H), 4.36-4.25 (m, 1H), 4.18-3.98 (m, 2H), 3.76-3.62 (m,1H), 2.96-2.82 (m, 2H), 1.58-1.44 (m, 2H), 1.36-1.18 (m, 4H), 0.92-0.77(m, 3H). The two CH₂ missing are hidden by the DMSO signal and the waterpeak.

Example 166-{(1E)-3-Oxo-3-[3-(pyridin-3-yloxy)pyrrolidin-1-yl]prop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E16) Step 1: tert-Butyl 3-(pyridin-3-yloxy)pyrrolidine-1-carboxylate

To a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (500 mg,2.67 mmol) in anhydrous THF (13 mL) under nitrogen were added3-hydroxypyridine (508 mg, 5.34 mmol) and triphenylphosphine (1.40 g,5.34 mmol). The reaction mixture was cooled to 0° C. and DEAD (775 μL,4.27 mmol) was added dropwise. The solution was allowed to warm to roomtemperature and stirred overnight. The reaction mixture was concentratedunder reduced pressure then diluted with dichloromethane and filtered.The filtrate was washed three times with NaOH 0.2N, dried over Na₂SO₄then concentrated. The residue was purified on column chromatography(eluent: pentane/acetone 9/1 to 7/3) to give the title compound (606 mg,86%) as a wax.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 8.35-8.23 (m, 1H), 8.22-8.12 (m,1H), 7.48-7.25 (m, 2H), 5.16-4.99 (m, 1H), 3.64-3.31 (m, 4H), 2.27-1.95(m, 2H), 1.49-1.28 (m, 9H). The desired product is contaminated withsome hydrogenated DEAD residue.

Step 2: 3-(Pyrrolidin-3-yloxy)pyridine hydrochloride

To a cooled solution of tert-butyl3-(pyridin-3-yloxy)pyrrolidine-1-carboxylate (600 mg, 2.27 mmol; whichmay be prepared as described in Step 1) in dichloromethane (15 mL) wasadded dropwise HCl 4N in dioxane (11.1 mL). The solution was warmed toroom temperature and stirred for 1 h. The solvent was evaporated underreduced pressure to give the title compound (263 mg, 58%) as a yellowwax.

LCMS (ESI+) m/z 165 (M+H (—HCl))⁺: 100%.

Step 3:6-{(1E)-3-Oxo-3-[3-(pyridin-3-yloxy)pyrrolidin-1-yl]prop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one

A 16 mL vial was successively charged with(2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride (40 mg, 0.16 mmol), DMF (3.8 mL),3-(pyrrolidin-3-yloxy)pyridine hydrochloride (64 mg, 0.32 mmol; whichmay be prepared as described in Step 2), DIPEA (63 μL, 0.38 mmol) andHATU (72 mg, 0.19 mmol). The reaction mixture was stirred at roomtemperature overnight and concentrated to dryness. The residue waspurified on chromatography column (eluent: dichloromethane/MeOH, 95/5)to give a beige solid. This solid was triturated in acetone and diethylether, filtered, washed with acetone and diethyl ether then dried togive the title compound (7.3 mg, 13%) as a beige solid.

LCMS (ESI+) m/z 365 (M+H)⁺: 100%.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 10.71-10.62 (m, 1H), 8.40-8.28 (m,2H), 8.24-8.17 (m, 1H), 8.02 (s, 1H), 7.51-7.41 (m, 2H), 7.40-7.32 (m,1H), 7.08-6.91 (m, 1H), 5.29-5.11 (m, 1H), 4.03-3.61 (m, 3.5H),3.55-3.41 (m, 0.5H), 2.98-2.84 (m, 2H), 2.33-2.03 (m, 2H). The CH₂missing is hidden by the DMSO signal.

Example 176-{(1E)-3-[3-(Benzyloxy)azetidin-1-yl]-3-oxoprop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E17) Step 1: 3-(Benzyloxy)-1-(diphenylmethyl)azetidine

To a solution of 1-diphenylmethylazetidin-3-ol (300 mg, 1.3 mmol) in DMF(2.6 mL) at 0° C. under nitrogen was added NaH (60% in oil, 56 mg, 1.4mmol). The suspension was stirred for 0.5 h at 0° C. then treated withbenzyl bromide (236 μL, 2.0 mmol). The mixture was allowed to warm toroom temperature then heated to 80° C. overnight. The reaction mixturewas cooled, acetic acid (20 drops) was added and the mixtureconcentrated under reduced pressure. The crude material was purified oncolumn chromatography (eluent: Pentane/EtOAc, 95/5 to 70/30) to give theproduct (104 mg, 24%) as an orange oil.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 7.47-7.12 (m, 15H), 4.40 (s, 1H),4.37 (s, 2H), 4.22-4.11 (m, 1H), 3.38-3.28 (m, 2H), 2.82-2.74 (m, 2H).

Step 2: 3-(Benzyloxy)azetidine hydrochloride

A 16 mL vial was charged with 3-(benzyloxy)-1-(diphenylmethyl)azetidine(103 mg, 0.31 mmol; which may be prepared as described in Step 1) and1,2-dichloroethane (1.4 mL). 1-Chloroethyl chloroformate (45 μL, 0.41mmol) was added and the reaction mixture was stirred at 70° C. for 1.5h. After cooling to room temperature, methanol (1.4 mL) was added andthe reaction mixture was stirred at 70° C. for 1.5 h. The reactionmixture was cooled and concentrated to dryness. The residue was purifiedon column chromatography (eluent: Pentane/NH₃ 7N in MeOH, 98/2) to givethe title compound (57 mg, 92%).

LCMS (ESI+) m/z 164 (M+H⁺ (—HCl)): 100%.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 7.40-7.23 (m, 5H), 4.36 (s, 2H),4.34-4.21 (m, 1H), 3.57-3.24 (m, 4H).

Step 3:6-{(1E)-3-[3-(Benzyloxy)azetidin-1-yl]-3-oxoprop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one

A 16 mL vial flask was successively charged with(2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride (60 mg, 0.24 mmol), DMF (5.8 mL), 3-(benzyloxy)azetidinehydrochloride (58 mg, 0.29 mmol; which may be prepared as described inStep 2), DIPEA (96 μL, 0.58 mmol), DMAP (2.4 mg, 0.02 mmol) and EDAC (56mg, 0.29 mmol). The reaction mixture was stirred at room temperatureovernight and concentrated to dryness. The residue was purified byprecipitation in MeOH/H₂O and then triturated in acetone/diethyl etherto give the title compound as a beige solid (33 mg, 38%).

LC-MS (ESI+) m/z 364 (M+H)⁺: 100%.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 10.66 (br s, 1H), 8.40-8.30 (m, 1H),8.06-7.97 (m, 1H), 7.46-7.26 (m, 6H), 6.71 (d, J=15.6 Hz, 1H), 4.53-4.35(m, 4H), 4.19-4.04 (m, 2H), 3.82-3.70 (m, 1H), 2.98-2.84 (m, 2H). TheCH₂ missing is hidden by the DMSO signal.

Example 186-{(1E)-3-[2-(1,3-Benzoxazol-2-yl)piperidin-1-yl]-3-oxoprop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E18) Step 1:tert-Butyl(2R)-2-{[(2-bromophenyl)amino]carbonyl}pyrrolidine-1-carboxylate

In a 500 mL flask, N-Boc-D-Proline (300 mg, 1.39 mmol) was dissolved indichloromethane (35 mL) and cooled to 0° C. under nitrogen.N-Methylmorpholine (153 μL, 1.39 mmol) was added followed by dropwiseaddition of iso-butyl chloroformate (180 μL, 1.39 mmol) and the reactionmixture stirred at 0° C. for 1 h. 2-Bromoaniline (1.31 mL, 1.39 mmol)was dissolved in dichloromethane (5 mL) then added quickly to theactivated acid at 0° C. The mixture was stirred overnight from 0° C. toroom temperature. The reaction mixture was diluted with dichloromethane,washed with water, dried over Na₂SO₄ and concentrated under reducedpressure. The crude mixture was purified on column chromatography(eluent: Pentane/EtOAc, 50/50 to 0/100 then EtOAc/MeOH 80/20) to givethe product (394 mg, 77%) as a yellow oil. This product was used in thenext step without further purification.

LCMS (ESI+) m/z 369 (M+)⁺: 7%.

Step 2: tert-Butyl(2R)-2-(1,3-benzoxazol-2-yl)pyrrolidine-1-carboxylate

In a 25 mL flask,tert-butyl(2R)-2-{[(2-bromophenyl)amino]carbonyl}pyrrolidine-1-carboxylate(194 mg, 0.53 mmol; which may be prepared as described in Step 1) wasdissolved in DME (4 mL) under nitrogen at room temperature. CuI (6 mg,0.03 mmol), Cs₂CO₃ (261 mg, 0.80 mmol) and 1,10-phenanthroline (26 mg,0.14 mmol) were added then the reaction mixture was heated at 85° C. for24 h. The mixture was cooled to room temperature and concentrated todryness. The residue was dissolved in dichloromethane and filtered onCelite to eliminate the copper residue. The filtrate was concentratedand the residue purified on preparative TLC (Pentane/EtOAc, 85/15 to50/50) to give the title compound (88 mg, 58%) as a solid.

LCMS (ESI+) m/z 289 (M+H)⁺: 9%.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 7.78-7.62 (m, 2H), 7.43-7.31 (m,2H), 5.08-4.94 (m, 1H), 4.60-4.34 (m, 2H), 2.42-1.80 (m, 4H), 1.37 (s,3H), 1.06 (s, 6H).

Step 3: 2-[(2R)-Pyrrolidin-2-yl]-1,3-benzoxazole trifluoroacetate

In a 16 mL flask, trifluoroacetic acid (4 mL) was added to a mixture oftert-butyl(2R)-2-(1,3-benzoxazol-2-yl)pyrrolidine-1-carboxylate (88 mg,0.31 mmol; which may be prepared as described in Step 2) dissolved indichloromethane (4 mL) at 0° C. under nitrogen. The reaction was allowedto warm to room temperature and stirred for 3 h. The reaction mixturewas concentrated to dryness and the residue used in the next stepwithout further purification.

LCMS (ESI+) m/z 189 (M+H)⁺: 100%.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 10.20-9.80 (m, 1H), 9.70-9.30 (m,1H), 7.88-7.77 (m, 2H), 7.54-7.41 (m, 2H), 5.17-5.05 (m, 1H), 3.45-3.33(m, 2H), 2.43-2.24 (m, 2H), 2.16-2.02 (m, 2H).

Step 4:6-{(1E)-3-[2-(1,3-Benzoxazol-2-yl)piperidin-1-yl]-3-oxoprop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one

A 16 mL vial flask was successively charged with(2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride (60 mg, 0.24 mmol), DMF (5.8 mL),2-[(2R)-pyrrolidin-2-yl]-1,3-benzoxazole trifluoroacetate (0.31 mmoltheory; which may be prepared as described in Step 3), DIPEA (96 μL,0.58 mmol), DMAP (2.4 mg, 0.02 mmol) and EDAC (56 mg, 0.29 mmol). Thereaction mixture was stirred at room temperature overnight andconcentrated to dryness. The residue was purified on preparative TLC(eluent: dichloromethane/MeOH, 95/5) and column chromatography (eluent:dichloromethane/MeOH, 98/2) to give the title compound (12 mg, 13%) as awhite solid.

LC-MS (ESI+) m/z 389 (M+H)⁺: 100%.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 10.71-10.51 (m, 1H), 8.45-8.18 (m,1H), 8.12-7.78 (m, 1H), 7.75-7.54 (m, 2H), 7.47-7.26 (m, 3H), 7.12-6.92(m, 1H), 5.83-5.71 (m, 0.2H), 5.31-5.16 (m, 0.8H), 4.04-3.56 (m, 2H),3.04-2.74 (m, 4H), 2.16-1.94 (m, 2H). The CH₂ missing is hidden by theDMSO signal.

Example 196-[(1E)-3-{3-[(2-Methylprop-2-en-1-yl)oxy]azetidin-1-yl}-3-oxoprop-1-en-1-yl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E19) Step 1:1-(Diphenylmethyl)-3-[(2-methylprop-2-en-1-yl)oxy]azetidine

A solution of 1-diphenylmethylazetidin-3-ol (239 mg, 1.0 mmol) in THF(3.6 mL) was cooled to 0° C. t-BuOK (1M in THF, 3.6 mL) was addeddropwise and the reaction mixture was stirred at room temperature for 1h then cooled to 0° C. 3-Bromo-2-methyl-1-propene (504 μL, 5.0 mmol) wasadded and the solution was stirred from 0° C. to room temperatureovernight. The reaction mixture was diluted with H₂O and extracted twicewith EtOAc. The organic layers were combined, dried over Na₂SO₄ andconcentrated to dryness to give the title compound (276 mg, 94%) as ayellow oil.

¹H NMR (CDCl₃, 300 MHz): δ (ppm): 7.50-7.07 (m, 10H), 4.89 (d, J=17.4Hz, 2H), 4.36 (br s, 1H), 4.21-4.10 (m, 1H), 3.77 (br s, 2H), 3.55-3.46(m, 2H), 2.95-2.85 (m, 2H), 1.72 (s, 3H).

Step 2: 3-[(2-Methylprop-2-en-1-yl)oxy]azetidine hydrochloride

A 16 mL flask was charged with1-(diphenylmethyl)-3-[(2-methylprop-2-en-1-yl)oxy]azetidine (276 mg,0.94 mmol; which may be prepared as described in Step 1) and1,2-dichloroethane (4.1 mL). 1-Chloroethyl chloroformate (135 μL, 1.24mmol) was added and the reaction mixture was stirred at 70° C. for 1.5h. After cooling to room temperature, methanol (4.1 mL) was added andthe reaction mixture was stirred at 70° C. for 1.5 h. The reactionmixture was concentrated to dryness and the residue was triturated inpentane to give the final product (192 mg, quantitative) as a brown oil.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 9.37-8.88 (m, 2H), 4.92 (d, J=20.2Hz, 2H), 4.40-4.28 (m, 1H), 4.15-4.03 (m, 2H), 3.88-3.72 (m, 4H), 1.67(s, 3H).

Step 3:6-[(1E)-3-{3-[(2-Methylprop-2-en-1-yl)oxy]azetidin-1-yl}-3-oxoprop-1-en-1-yl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one

A 16 mL vial flask was successively charged with(2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride (60 mg, 0.24 mmol), DMF (5.8 mL),3-[(2-methylprop-2-en-1-yl)oxy]azetidine hydrochloride (78 mg, 0.48mmol; which may be prepared as described in Step 2), DIPEA (119 μL, 0.72mmol), DMAP (2.4 mg, 0.02 mmol) and EDAC (56 mg, 0.29 mmol). Thereaction mixture was stirred at room temperature overnight andconcentrated to dryness. The residue was precipitated in methanol/waterand then filtered. The resulting solid was dissolved in chloroform andwashed with water to give a beige solid. This solid was triturated indiethyl ether to give the title compound (13 mg, 16%) as a white solid.

LCMS (ESI+) m/z 328 (M+H)⁺: 100%.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 10.67 (br s, 1H), 8.41-8.29 (m, 1H),8.06-7.96 (m, 1H), 7.39 (d, J=15.9 Hz, 1H), 6.71 (d, J=15.9 Hz, 1H),5.03-4.94 (m, 1H), 4.92-4.82 (m, 1H), 4.53-4.42 (m, 1H), 4.41-4.27 (m,1H), 4.21-4.03 (m, 2H), 3.88-3.69 (m, 3H), 2.95-2.84 (m, 2H), 1.69 (m,3H). The CH₂ missing is hidden by the DMSO signal.

Example 206-{(1E)-3-Oxo-3-[3-(1,3-thiazol-2-ylmethoxy)azetidin-1-yl]prop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E20) Step 1: 2-(Chloromethyl)-1,3-thiazol-3-ium chloride

In a 50 mL flask, thiazole-2-methanol (500 mg, 4.3 mmol) was dissolvedin THF (2.6 mL) and cooled to 0° C. under nitrogen. Thionyl chloride(377 μL, 5.2 mmol) was added dropwise and the reaction mixture wasallowed to warm to room temperature then heated at 50° C. for 2 h. Thecrude mixture was concentrated under reduced pressure to give an orangesolid (684 mg, 94%).

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 7.88-7.76 (m, 2H), 5.16-5.01 (m,2H).

Step 2: tert-Butyl 3-(1,3-thiazol-2-ylmethoxy)azetidine-1-carboxylate

To a solution of N-Boc-azetidin-3-ol (260 mg, 1.5 mmol) in DMF (3.5 mL)at 0° C. under nitrogen was added NaH (60% in oil, 126 mg, 3.15 mmol).The suspension was stirred for 0.5 h at 0° C. then treated with2-(chloromethyl)-1,3-thiazol-3-ium chloride (510 mg, 3.0 mmol; which maybe prepared as described in Step 1) dissolved in DMF (1 mL) and DIPEA(1.05 mL). The mixture was allowed to warm to room temperature thenheated to 80° C. overnight. The reaction mixture was cooled, water (20drops) was added and the mixture concentrated under reduced pressure.The crude material was purified on column chromatography (eluent:Pentane/EtOAc, 90/10 to 50/50) to give the product (193 mg, 48%) as abrown oil.

LCMS (ESI+) m/z 271 (M+H)⁺: 100%.

Step 3: 2-[(Azetidin-3-yloxy)methyl]-1,3-thiazole hydrochloride

To a solution of tert-butyl3-(1,3-thiazol-2-ylmethoxy)azetidine-1-carboxylate (193 mg, 0.71 mmol;which may be prepared as described in Step 2) dissolved in diethyl ether(2.6 mL) at room temperature was added HCl 2N in diethyl ether (7.1 mL).The reaction mixture was stirred for 1.5 h then concentrated to dryness.The resulting solid was triturated with diethyl ether, collected anddried to give the title compound (138 mg, quantitative) as a brown oil.

¹H NMR (CDCl₃, 300 MHz): δ (ppm): 9.40-8.90 (m, 2H), 7.89-7.71 (m, 2H),4.83 (s, 2H), 4.64-4.59 (m, 1H), 4.18-4.03 (m, 2H), 3.91-3.79 (m, 2H).

Step 4:6-{(1E)-3-Oxo-3-[3-(1,3-thiazol-2-ylmethoxy)azetidin-1-yl]prop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one

A 16 mL vial flask was successively charged with(2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride (60 mg, 0.24 mmol), DMF (5.8 mL),2-[(azetidin-3-yloxy)methyl]-1,3-thiazole hydrochloride (99 mg, 0.48mmol; which may be prepared as described in Step 3), DIPEA (119 μL, 0.72mmol), DMAP (2.4 mg, 0.02 mmol) and EDAC (56 mg, 0.29 mmol). Thereaction mixture was stirred at room temperature overnight andconcentrated to dryness. The residue was precipitated in methanol/waterand then filtered. The resulting solid was purified on columnchromatography (eluent: 96/4 dichloromethane/MeOH) then triturated inpentane and MeOH to give the title compound (21 mg, 24%) as a whitesolid.

LCMS (ESI+) m/z 371 (M+H)⁺: 100%.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 10.66 (br s, 1H), 8.40-8.29 (m, 1H),8.03-7.99 (m, 1H), 7.84-7.74 (m, 2H), 7.40 (d, J=15.6 Hz, 1H), 6.72 (d,J=15.5 Hz, 0.9H), 6.48 (d, J=16.0 Hz, 0.1H), 4.82 (s, 2H), 4.61-4.45 (m,2H), 4.20-4.11 (m, 2H), 3.85-3.74 (m, 1H), 2.95-2.84 (m, 2H). The CH₂missing is hidden by the DMSO signal.

Example 216-{(1E)-3-[3-({[(1E)-1-Methyl-2-pyrimidin-2-ylethylidene]amino}oxy)azetidin-1-yl]-3-oxoprop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E21) Step 1: 1-Pyrimidin-2-ylacetone

In a 100 mL flask, acetone (1.44 mL, 19.6 mmol) was added to KH (30% inoil, 2.89 g, 21.6 mmol) in THF (15 mL) at 0° C. under nitrogen. Thereaction mixture was stirred for 0.25 h then additional THF (15 mL) wasadded. AIBN (74 mg, 0.45 mmol) followed by 2-chloropyrimidine (500 mg,4.36 mmol) were added cautiously and the reaction mixture kept at 0° C.for 1 h. HCl 3N was added until the pH=6. The two layers were separatedand the aqueous phase extracted with dichloromethane. The combinedextracts were dried over Na₂SO₄ then concentrated. The residue waspurified on column chromatography (eluent: EtOAc/pentane 20/80 to 80/20)to give the title compound (247 mg, 42%) as a yellow oil (keto/enol form2:1).

LCMS (ESI+) m/z 137 (M+H)⁺: 100%.

¹H NMR (CDCl₃, 300 MHz): δ (ppm): 13.71-13.67 (m, 0.3H), 8.71 (d, J=5.0Hz, 2H), 8.60-8.48 (m, 0.8H), 7.21 (t, J=5.0 Hz, 1H), 6.97-6.87 (m,0.4H), 5.57 (br s, 0.4H), 4.13 (s, 2H), 2.29 (s, 3H), 2.09 (s, 1.2H).

Step 2:2-{[1-(Diphenylmethyl)azetidin-3-yl]oxy}-1H-isoindole-1,3(2H)-dione

To a solution of N-benzhydrylazetidin-3-ol (1.0 g, 4.18 mmol) inanhydrous THF (66 mL) under nitrogen were added N-hydroxyphthalimide(750 mg, 4.60 mmol) and triphenylphosphine (2.19 g, 8.36 mmol). Thereaction mixture was cooled to 0° C. and DEAD (1.52 mL, 8.36 mmol) wasadded dropwise. The solution was allowed to warm to room temperature andstirred overnight. The reaction mixture was concentrated under reduced.The residue was purified on column chromatography (eluent: pentane/EtOAc7/3 to 4/6) to give the title compound (600 mg, 37%) as a wax.

LCMS (ESI+) m/z 385 (M+H)⁺: 100%.

¹H NMR (CDCl₃, 300 MHz): δ (ppm): 7.88-7.79 (m, 2H), 7.78-7.68 (m, 2H),7.50-7.35 (m, 4H), 7.30-7.25 (m, 4H), 7.20-7.00 (m, 2H), 4.97-4.86 (m,1H), 4.49 (s, 1H), 3.62-3.50 (m, 2H), 3.40-3.26 (m, 2H).

Step 3: 3-(Aminooxy)-1-(diphenylmethyl)azetidine

To a solution of2-{[1-(diphenylmethyl)azetidin-3-yl]oxy}-1H-isoindole-1,3(2H)-dione (600mg, 1.56 mmol; which may be prepared as described in Step 2) in ethanol(13.3 mL) was added hydrazine hydrate (100 μL, 2.06 mmol). The resultingmixture was heated to reflux for 2 h then concentrated under reducedpressure. The residue was taken up in dichloromethane/methanol mixturethen filtered. The filtrate was concentrated and the residue purified oncolumn chromatography (eluent: Dichloromethane/NH₃ 7N in MeOH, 2% to 5%)to give the title compound (307 mg, 77%) as a clear oil.

LCMS (ESI+) m/z 255 (M+H)⁺: 100%.

Step 4: (2E)-1-Pyrimidin-2-ylacetoneO-(1-diphenylmethylazetidin-3-yl)oxime

A solution of 1-pyrimidin-2-ylacetone (27 mg, 0.2 mmol; which may beprepared as described in Step 1) and3-(aminooxy)-1-(diphenylmethyl)azetidine (51 mg, 0.2 mmol; which may beprepared as described in Step 3) in ethanol (2 mL) under nitrogen wasstirred at 80° C. overnight. The crude mixture was concentrated todryness to give the title compound (75 mg, quantitative) as a brown oil.

LC-MS (ESI+) m/z 373 (M+H)⁺: 100%.

¹H NMR (CDCl₃, 300 MHz): δ (ppm): 8.69 (dd, J=5.1, 1.5 Hz, 2H),7.51-7.31 (m, 6H), 7.26-7.11 (m, 5H), 4.98-4.73 (m, 1H), 4.54-4.30 (m,1H), 4.07 (s, 1H), 3.84 (s, 1H), 3.67-3.40 (m, 2H), 3.18-2.91 (m, 2H),1.91 (s, 3H).

Step 5: (2E)-1-Pyrimidin-2-ylacetone O-azetidin-3-yloxime hydrochloride

A 25 mL flask was charged with (2E)-1-pyrimidin-2-ylacetoneO-(1-diphenylmethylazetidin-3-yl)oxime (372 mg, 1.0 mmol; which may beprepared as described in Step 4) and 1,2-dichloroethane (8.8 mL).1-Chloroethylchloroformate (576 μL, 5.28 mmol) was added and thereaction mixture was heated to 70° C. for 3 h. After cooling to roomtemperature, methanol (8.8 mL) was added and the reaction mixture washeated to 70° C. for 3 h. The reaction mixture was concentrated todryness and the crude mixture triturated in pentane and diethyl ether togive the title compound (240 mg, 99%) as a dark solid.

LCMS (ESI+) m/z 207 (M+H (—HCl))⁺: 17%.

Step 6:6-{(1E)-3-[3-({[(1)-1-Methyl-2-pyrimidin-2-ylethylidene]amino}oxy)azetidin-1-yl]-3-oxoprop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one

A 16 mL vial was successively charged with(2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride (60 mg, 0.24 mmol), DMF (6 mL),(2E)-1-pyrimidin-2-ylacetone O-azetidin-3-yloxime hydrochloride (117 mg,0.48 mmol; which may be prepared as described in Step 5), DIPEA (160 μL,0.96 mmol) and DMAP (3 mg, 0.024 mmol). The reaction mixture was cooledto 0° C. and EDAC (56 mg, 0.29 mmol) was added. The reaction mixture wasallowed to warm to room temperature, stirred overnight then concentratedto dryness. The crude mixture was purified on column chromatography(eluent: dichloromethane/MeOH, 2% to 6%) then triturated in diethylether and dichloromethane to give the product (8 mg, 8%) and as a beigesolid.

LCMS (ESI+) m/z 407 (M+H)⁺: 100%.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 10.66 (br s, 1H), 8.82-8.71 (2×d,J=4.8 Hz, 1H), 8.40-8.31 (m, 1H), 8.08-7.98 (m, 1H), 7.52-7.17 (m, 3H),6.81-6.65 (2×d, J=15.9 Hz, 1H), 5.18-4.99 (m, 1H), 4.60-4.40 (m, 1H),4.32-4.13 (m, 2H), 4.12-4.06 (m, 1H), 4.04-3.77 (m, 2H), 2.98-2.86 (m,2H), 1.90-1.85 (2×s, 3H). The CH₂ missing is hidden by the DMSO signal.

Example 226-{(1E)-3-[3-(Pentylsulfonyl)azetidin-1-yl]-3-oxoprop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E22) Step 1: 1-(Diphenylmethyl)azetidin-3-yl methanesulfonate

To a solution of dibenzylazetidin-3-ol (500 mg, 2.09 mmol) in THF (21mL) at 0° C. under nitrogen was added methanesulfonyl chloride (194 μL,2.51 mmol) and triethylamine (612 μL, 4.39 mmol). The reaction mixturewas stirred for 1 h then concentrated to dryness. The residue wasdissolved in dichloromethane, washed with water and brine. The organiclayer was dried over Na₂SO₄, filtered and concentrated to dryness togive the title product (0.61 g, 92%) as a yellow oil.

LCMS (ESI+) m/z 318 (M+H)⁺: 20%.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 7.45-7.14 (m, 10H), 5.16-5.05 (m,1H), 4.40 (s, 1H), 3.67-3.58 (m, 2H), 3.25-3.14 (m, 2H), 2.99 (s, 3H).

Step 2: 1-(Diphenylmethyl)-3-(pentylthio)azetidine

To a solution of pentanethiol (248 μL, 2.0 mmol) in DMSO (2.5 mL) at 0°C. under nitrogen was added NaH (60% in oil, 80 mg, 2.0 mmol). Thesuspension was stirred for 0.5 h at 0° C. then treated with1-(diphenylmethyl)azetidin-3-yl methanesulfonate (317 mg, 1.0 mmol;which may be prepared as described in Step 1) and the mixture allowed towarm to room temperature overnight. Saturated NaHCO₃ (5 mL) was addedand the mixture was extracted with diethyl ether. The organic layer wasseparated from the aqueous and the organic washed with brine, dried overNa₂SO₄ and concentrated to give the product (312 mg, 96%) as a yellowoil.

¹H NMR (CDCl₃, 300 MHz): δ (ppm): 7.83-7.69 (m, 10H), 4.39 (br s, 1H),3.63-3.49 (m, 3H), 3.01-2.90 (m, 2H), 2.61 (br s, 2H), 2.53-2.43 (m,2H), 1.56-1.45 (m, 2H), 1.35-1.27 (m, 4H), 0.93-0.82 (m, 3H).

Step 3: 1-(Diphenylmethyl)-3-(pentylsulfonyl)azetidine

To a solution of 1-(diphenylmethyl)-3-(pentylthio)azetidine (228 mg,0.70 mmol; which may be prepared as described in Step 2) in methanol(6.3 mL) and water (6.3 mL) was added H₂SO₄ 1N (0.7 mL). The reactionmixture was stirred for 10 minutes, then oxone (1.08 g, 1.75 mmol) wasadded and the mixture stirred at room temperature for 12 h. A solutionof saturated NaHCO₃ (5 mL) was added and the mixture extracted withethyl acetate. The two layers were separated and the organic washed withbrine, dried over Na₂SO₄, filtered and concentrated. The crude was thenpurified on column chromatography (pentane/EtOAc, 100/0 then 90/10) togive the title product (75 mg, 30%) as a pale yellow oil. The less purefraction (N-oxide) can be recycled in hydrogenolysis conditions.

LC-MS (ESI+) m/z 358 (M+H)⁺: 100%.

¹H NMR (CDCl₃, 300 MHz): δ (ppm): 7.45-7.15 (m, 10H), 4.51 (s, 1H),3.97-3.84 (m, 1H), 3.58-3.42 (m, 4H), 2.92-2.83 (m, 2H), 1.84-1.70 (m,2H), 1.43-1.27 (m, 4H), 0.93-0.85 (m, 3H).

Step 4: 3-(Pentylsulfonyl)azetidine hydrochloride

A 16 mL flask was charged with1-(diphenylmethyl)-3-(pentylsulfonyl)azetidine (136 mg, 0.38 mmol; whichmay be prepared as described in Step 3) and 1,2-dichloroethane (1.7 mL).1-Chloroethyl chloroformate (53 μL, 0.49 mmol) was added and thereaction mixture was stirred at 70° C. for 1.5 h. After cooling to roomtemperature, methanol (1.7 mL) was added and the reaction mixturestirred at 70° C. for 1.5 h. The reaction mixture was concentrateddryness. LCMS analysis showed a mixture of the final product and thestarting material. The residue was dissolved again in 1,2-dichloroethaneand 1-chloroethyl chloroformate (4 eq., 164 μL) was added. The reactionmixture was stirred at 70° C. for 5 h and overnight after addition ofmethanol. No starting material was detected by TLC monitoring, so thereaction mixture was concentrated to dryness and the resulting solidtriturated in pentane to give the title product (39 mg, 45%) as a darkorange oil.

LCMS (ESI+) m/z 192 (M+H(—HCl))⁺: 100%.

Step 5:6-{(1E)-3-[3-(Pentylsulfonyl)azetidin-1-yl]-3-oxoprop-1-en-1-yl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one

A 16 mL vial flask was successively charged with(2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride (40 mg, 0.16 mmol), DMF (3.9 mL),3-(pentylsulfonyl)azetidine hydrochloride (39 mg, 0.17 mmol; which maybe prepared as described in Step 4), DIPEA (106 μL, 0.64 mmol), DMAP (2mg, 0.02 mmol) and EDAC (36 mg, 0.19 mmol). The reaction mixture wasstirred at room temperature overnight and concentrated to dryness. Theresidue was purified on preparative TLC (eluent: 90/10 DCM/MeOH) thentriturated in pentane with a drop of acetone to give the title compound(12 mg, 19%) as a white solid.

LCMS (ESI+) m/z 392 (M+H)⁺: 100%.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 10.68 (br s, 1H), 8.41-8.25 (m, 1H),8.06-7.76 (m, 1H), 7.50-7.36 (m, 1H), 6.84-5.94 (m, 1H), 4.63-4.03 (m,4H), 3.23-3.11 (m, 2H), 2.97-2.85 (m, 2H), 1.72-1.45 (m, 2H), 1.43-1.22(m, 4H), 0.92-0.80 (m, 3H). The CH₂ missing is hidden by the DMSOsignal.

Example 235-{(1E)-3-Oxo-3-[3-(pyridin-4-ylmethoxy)azetidin-1-yl]prop-1-en-1-yl}pyridin-2-amine(E23) Step 1: tert-Butyl(2E)-3-(6-aminopyridin-3-yl)acrylate

To a solution of 2-amino-5-bromopyridine (300 mg, 1.73 mmol) in DMF (1.5mL) and proprionitrile (3.5 mL) under Argon were added DIPEA (613 μL,3.71 mmol), tert-butyl acrylate (1.02 mL, 7.06 mmol),tri(o-tolyl)phosphine (106 mg, 0.35 mmol) and palladium acetate (39 mg,0.17 mmol). The mixture was stirred at 100° C. for 20 h, then allowed tocome back to room temperature, filtered through Celite pad and rinsedwith EtOAc. The residue obtained after concentration was purified byflash chromatography (eluent: 95/5 DCM/MeOH) to give the title compoundas an orange solid (380 mg, quantitative).

LCMS (ESI+) m/z 221 (M+H)⁺: 100%.

Step 2: (2E)-3-(6-Aminopyridin-3-yl)acrylic acid hydrochloride

To a solution of tert-butyl(2E)-3-(6-aminopyridin-3-yl)acrylate (380 mg,1.73 mmol; which may be prepared as described in Step 1) in DCM (3.45mL) under Argon was added trifluoroacetic acid (3.45 mL). The mixturewas stirred at room temperature for 1 h, then HCl 4N in dioxane (6.9 mL)was added. A beige solid started precipitating at the half of theaddition. After concentration, the solid was triturated in Et₂O,filtered, rinsed with Et₂O and dried under vacuum to give the titlecompound as a beige solid (265 mg, 76%).

LCMS (ESI+) m/z 165 (M-(HCl)+H)⁺: 100%.

Step 3: tert-Butyl 3-(pyridin-4-ylmethoxy)azetidine-1-carboxylate

A solution of N-Boc-azetidin-3-ol (500 mg, 2.89 mmol) in THF (10 mL) wascooled to 0° C. t-BuOK (1M in THF, 11.6 mL) was added dropwise and thereaction mixture was stirred at room temperature for 0.25 h then cooledto 0° C. A solution of 4-bromomethylpyridine hydrobromide (2.19 g, 8.67mmol) in dichloromethane (5 mL) stirred with DIPEA (4 mL, 24 mmol) for0.5 h was then added. The reaction mixture was stirred at roomtemperature for 24 h. The reaction mixture was diluted with H₂O andextracted twice with EtOAc. The organics were separated from the aqueouslayer and combined, dried over Na₂SO₄ and concentrated to dryness. Thecrude mixture was purified by column chromatography (eluent:Pentane/EtOAc, 1/1 to 7/3) to give the title product (313 mg, 41%) as ayellow oil.

LCMS (ESI+) m/z 265 (M)⁺: 28%.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 8.54 (d, J=5.9 Hz, 2H), 7.34 (d,J=5.9 Hz, 2H), 4.49 (s, 2H), 4.39-4.25 (m, 1H), 4.06-3.90 (m, 2H),3.80-3.65 (m, 2H), 1.37 (s, 9H).

Step 4: 4-[(Azetidin-3-yloxy)methyl]pyridine dihydrochloride

To a solution of tert-butyl3-(pyridin-4-ylmethoxy)azetidine-1-carboxylate (313 mg, 1.18 mmol; whichmay be prepared as described in Step 3) in diethyl ether (4 mL) at 0° C.was added HCl 2N in diethyl ether (12 mL). The reaction mixture wasstirred for 1 h then mixture was filtered. The resulting solid wasrinsed with diethyl ether and collected to give the title compound as awhite solid (155 mg, 65%).

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 9.76-9.17 (m, 2H), 8.92-8.84 (m,2H), 8.01-7.88 (m, 2H), 4.81 (s, 2H), 4.60-4.46 (m, 1H), 4.23-4.09 (m,2H), 3.98-3.84 (m, 2H).

Step 5:5-{(1E)-3-Oxo-3-[3-(pyridin-4-ylmethoxy)azetidin-1-yl]prop-1-en-1-yl}pyridin-2-amine

To a solution of (2E)-3-(6-aminopyridin-3-yl)acrylic acid hydrochloride(42 mg, 0.21 mmol; which may be prepared as described in Step 2) in DMF(5 mL) were added 4-[(azetidin-3-yloxy)methyl]pyridine dihydrochloride(50 mg, 0.25 mmol; which may be prepared as described in Step 4), DIPEA(171 μL, 1.04 mmol), DMAP (2.5 mg, 0.02 mmol) and EDAC (48 mg, 0.25mmol). The reaction mixture was stirred at room temperature overnightand concentrated to dryness. The residue was partitioned between aNaHCO₃ 5% solution and DCM. The aqueous phase was extracted twice withDCM, dried over sodium sulfate, filtered and concentrated under vacuumto give an orange solid. The crude was purified on preparative TLC(eluent: 90/10 DCM/MeOH+1% NH₄OH) to give the title compound (21 mg,33%) as a pale yellow solid.

LCMS (ESI+) m/z 156 (M/2+H)²⁺: 100%; m/z 311 (M+H)⁺: 25%.

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 8.55 (dd, J=1.5, 4.4 Hz, 2H), 8.12(d, J=2.2 Hz, 1H), 7.75 (dd, J=2.4, 8.8 Hz, 1H), 7.36 (dd, J=1.5, 4.4Hz, 2H), 7.29 (d, J=15.7 Hz, 1H), 6.47-6.41 (m, 4H), 4.54 (s, 2H),4.48-4.43 (m, 2H), 4.16-4.09 (m, 2H), 3.83-3.76 (m, 1H)

Example 24N-(5-{(1E)-3-Oxo-3-[3-(pyridin-4-ylmethoxy)azetidin-1-yl]prop-1-en-1-yl}pyridin-2-yl)acetamide(E24)

To a solution of5-{(1E)-3-oxo-3-[3-(pyridin-4-ylmethoxy)azetidin-1-yl]prop-1-en-1-yl}pyridin-2-amine(16 mg, 0.05 mmol) and acetic anhydride (6 μL, 0.06 mmol) in THF (2.4mL) was added NaHCO₃ (5.5 mg, 0.065 mmol). The reaction mixture waswarmed at 60° C. and stirred for 40 h. LCMS showed that some startingmaterial was remaining. Another portion of acetic anhydride (6 μL) andNaHCO₃ (5.5 mg) were added and the mixture was stirred at 60° C. for 24h. These additions were repeated twice over 48 h. The mixture was thenconcentrated, partitioned between water and ethyl acetate. The aqueouslayer was extracted twice with ethyl acetate. The combined organiclayers were washed with brine, dried over sodium sulfate, filtered andconcentrated under vacuum to give an oil. The crude was purified onpreparative TLC (eluent: 90/10 DCM/MeOH) to give the title compound (2.3mg, 12%) as a pale yellow solid.

LCMS (ESI+) m/z 177 (M/2+H)²⁺: 100%; m/z 353 (M+H)⁺: 22%.

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 10.66 (s, 1H), 8.58-8.54 (m, 3H),8.14-8.07 (m, 2H), 7.42 (d, J=15.7 Hz, 1H), 7.37 (d, J=5.9 Hz, 2H), 6.76(d, J=15.7 Hz, 1H), 4.54 (s, 2H), 4.53-4.45 (m, 2H), 4.21-4.13 (m, 2H),3.86-3.80 (m, 1H), 2.10 (s, 3H)

Example 25 Methyl6-[(1E)-3-{4-[(4-fluorophenoxy)methyl]piperidin-1-yl}-3-oxoprop-1-en-1-yl]-2-oxo-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate(E25) Step 1: tert-Butyl4-[(4-fluorophenoxy)methyl]piperidine-1-carboxylate

4-Fluorophenol (520 mg, 4.64 mmol) and triphenylphosphine (1.22 g, 4.64mmol) were added to a solution of N-boc-piperidine-4-methanol (500 mg,2.32 mmol) in anhydrous THF (12 mL) under nitrogen. The reaction mixturewas cooled to 0° C. and DEAD (670 μL, 3.69 mmol) was added dropwise. Thesolution was allowed to warm to room temperature and stirred overnight.The reaction mixture was concentrated under reduced pressure thendiluted with dichloromethane and filtered. The filtrate was washed threetimes with NaOH 0.2N, dried over Na₂SO₄ and concentrated. The residuewas purified on column chromatography (eluent: pentane/EtOAc 95/5) togive the title compound (538 mg, 75%) as a yellow oil.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 7.17-7.02 (m, 2H), 6.98-6.88 (m,2H), 4.02-3.88 (m, 2H), 3.79 (d, J=6.3 Hz, 2H), 2.83-2.60 (m, 2H),1.96-1.79 (m, 1H), 1.79-1.64 (m, 2H), 1.39 (s, 9H), 1.23-1.04 (m, 2H).

Step 2: 4-[(4-Fluorophenoxy)methyl]piperidine hydrochloride

To a cooled solution of tert-butyl4-[(4-fluorophenoxy)methyl]piperidine-1-carboxylate (538 mg, 1.74 mmol;which may be prepared as described in Step 1) in dichloromethane (11.5mL) was added dropwise HCl 4N in dioxane (8.5 mL). The solution waswarmed to room temperature and stirred for 1 h. The solvent wasevaporated under reduced pressure to give the title compound (416 mg,97%) as a white solid.

¹H NMR (DMSO-d₆, 300 MHz): δ (ppm): 9.12-8.88 (m, 1H), 8.80-8.56 (m,1H), 7.17-7.02 (m, 2H), 7.01-6.86 (m, 2H), 3.82 (d, J=6.6 Hz, 2H),3.32-3.21 (m, 2H), 2.97-2.78 (m, 2H), 2.10-1.95 (m, 1H), 1.94-1.81 (m,2H), 1.58-1.37 (m, 2H).

Step 3: Methyl6-[(1E)-3-tert-butoxy-3-oxoprop-1-en-1-yl]-2-oxo-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate

To a suspension of methyl6-bromo-2-oxo-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate (300mg, 1.06 mmol), prepared as in J. Med. Chem. 2003, 46, 9, 1627-1635, inDMF (1 mL) and proprionitrile (3.5 mL) under Argon were added DIPEA (175μL, 2.271 mmol), tert-butyl acrylate (615 mL, 4.24 mmol),tri(o-tolyl)phosphine (64 mg, 0.21 mmol) and palladium acetate (48 mg,0.21 mmol). The mixture was stirred at 100° C. overnight. LCMS analysisshowed that some unreacted starting material was remaining, so 24 mg ofpalladium acetate and 64 mg of tri(o-tolyl)phosphine were added. After 5h at 100° C., the reaction was allowed to come back to room temperature,filtered through Celite pad and rinsed with methanol. The residueobtained after concentration was purified by flash chromatography(eluent: gradient DCM/EtOAc) to give the title compound as an orangesolid (115 mg, 32%) contaminated with traces of tri(o-tolyl)phosphineoxide.

LCMS (ESI+) m/z 333 (M+H)⁺: 100%.

Step 4:(2E)-3-[6-(Methoxycarbonyl)-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl]acrylicacid

To a solution of methyl6-[(1E)-3-tert-butoxy-3-oxoprop-1-en-1-yl]-2-oxo-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate(115 mg, 0.346 mmol; which may be prepared as described in Step 3) inDCM (693 μL) at 0° C. under Argon was added TFA (693 μL). The reactionwas allowed to come back to room temperature under stirring for 2 h andthen concentrated under vacuo to give the title compound (103 mg,quantitative) as a brown solid. The product was used without furtherpurification.

LCMS (ESI+) m/z 277 (M+H)⁺: 100%.

Step 5: Methyl6-[(1E)-3-{4-[(4-fluorophenoxy)methyl]piperidin-1-yl}-3-oxoprop-1-en-1-yl]-2-oxo-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate

To a solution of(2E)-3-[6-(methoxycarbonyl)-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl]acrylicacid (96 mg, 0.35 mmol; which may be prepared as described in Step 4) inDMF (8 mL) were added 4-[(4-fluorophenoxy)methyl]piperidinehydrochloride (102 mg, 0.42 mmol; which may be prepared as described inStep 2), DIPEA (144 μL, 0.83 mmol), 4-DMAP (17 mg, 0.14 mmol) and EDAC(80 mg, 0.42 mmol). The reaction mixture was stirred at room temperatureovernight and concentrated to dryness. The residue was purified by flashchromatography on silica gel (eluent: dichloromethane/MeOH from 100/0 to80/20) to give a first solid which is purified again on preparative TLC(eluent: dichloromethane/MeOH 95/5) to give the title compound (15 mg,8%) as a white solid.

LCMS (ESI+) m/z 468 (M+H)⁺: 100%.

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 10.23 (s, 1H), 8.44 (s, 1H), 7.69 (s,1H), 7.60 (d, J=16.0 Hz, 1H), 6.99-6.89 (m, 3H), 6.83-6.80 (m, 2H),4.85-4.71 (m, 1H), 4.21-4.10 (m, 1H), 3.84-3.74 (m, 5H), 3.71 (t, J=6.9Hz, 1H), 3.45-3.38 (m, 1H), 3.20-3.14 (m, 2H), 2.80-2.68 (m, 1H),2.15-2.03 (m, 1H), 2.03-1.88 (m, 2H), 1.40-1.34 (m, 2H).

Examples 26 and 276-[(1E)-3-{4-[(4-Fluorophenoxy)methyl]piperidin-1-yl}-3-oxoprop-1-en-1-yl]-2-oxo-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxamide(E26); and6-[(1E)-3-{4-[(4-Fluorophenoxy)methyl]piperidin-1-yl}-3-oxoprop-1-en-1-yl]-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide(E27)

A solution of methyl6-[(1E)-3-{4-[(4-fluorophenoxy)methyl]piperidin-1-yl}-3-oxoprop-1-en-1-yl]-2-oxo-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate(13 mg, 0.028 mmol) in ammonium hydroxide (33% in water, 0.5 mL) and inammonia (2M in ethanol, 0.5 mL) was stirred at 90° C. for 1 h30. Themixture was concentrated to dryness and the residue was purified onpreparative TLC (eluent: dichloromethane/MeOH 90/10) to give6-[(1E)-3-{4-[(4-fluorophenoxy)methyl]piperidin-1-yl}-3-oxoprop-1-en-1-yl]-2-oxo-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxamide(1.6 mg, 12%) as a white solid.

LCMS (ESI+) m/z 453 (M+H)⁺: 100%.

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 8.52 (s, 1H), 8.29 (s, 1H), 7.77 (s,1H), 7.60 (d, J=16.0 Hz, 1H), 7.17 (br s, 1H), 7.02-6.94 (m, 2H), 6.90(d, J=15.0 Hz, 1H), 6.85-6.80 (m, 2H), 5.50 (br s, 1H), 4.84-4.72 (m,1H), 4.22-4.12 (m, 1H), 3.84-3.74 (m, 2H), 3.56 (t, J=7.4 Hz, 1H),3.50-3.38 (m, 1H), 3.31-3.14 (m, 2H), 2.80-2.70 (m, 1H), 2.16-1.88 (m,3H), 1.44-1.32 (m, 2H).

The second isolated fraction gave the oxidized derivative(6-[(1E)-3-{4-[(4-fluorophenoxy)methyl]piperidin-1-yl}-3-oxoprop-1-en-1-yl]-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide)as a white solid (2.3 mg, 18%).

LCMS (ESI+) m/z 451 (M+H)⁺: 100%.

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 12.92 (s, 1H), 9.00 (d, J=2.0 Hz,1H), 8.90 (d, J=3.9 Hz, 1H), 8.79-8.77 (m, 2H), 7.84 (d, J=4.3 Hz, 1H),7.55 (d, J=15.0 Hz, 1H), 7.44 (d, J=15.0 Hz, 1H), 7.13-7.08 (m, 2H),6.97-6.93 (m, 2H), 4.58-4.50 (m, 1H), 4.40-4.32 (m, 1H), 3.84 (d, J=6.4Hz, 2H), 3.22-3.12 (m, 1H), 2.77-2.68 (m, 1H), 2.12-1.96 (m, 1H),1.92-1.80 (m, 2H), 1.30-1.12 (m, 2H).

Example 283-(Hydroxymethyl)-6-[(1E)-3-{4-[(4-fluorophenoxy)methyl]piperidin-1-yl}-3-oxoprop-1-en-1-yl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E28) Step 1: 1-Acryloyl-4-[(4-fluorophenoxy)methyl]piperidine

To a solution of acrylic acid (34 μL, 0.49 mmol) in dichloromethane (2.4mL) cooled at 0° C. was added 4-methylmorpholine (134 μL, 1.22 mol) andisobutyl chloroformate (74 μL, 0.57 mmol). The solution was stirred 15minutes at 0° C. and then 4-[(4-fluorophenoxy)methyl]piperidinehydrochloride (100 mg, 0.41 mmol) was added. The mixture was stirred atroom temperature overnight, diluted with water (7 mL) and extractedtwice with DCM (2×5 mL). The combined organic phases were washed withwater, dried over sodium sulphate and concentrated in vacuo. The residueobtained was purified by preparative TLC (eluent: dichloromethane/MeOH95/5) to give the title compound (30 mg, 28%) as a yellow oil.

LCMS (ESI+) m/z 264 (M+H)⁺: 100%.

Step 2: 6-Bromo-3-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one

To a suspension of methyl6-bromo-2-oxo-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate (285mg, 1 mmol) in THF (10 mL) under Argon at room temperature was addedsodium borohydride (151 mg, 4 mmol). The reaction mixture was stirred at60° C. for 4 h, then diluted in EtOAc and washed four times with a NH₄Clsolution (pH=6.5). The white organic phase was filtered to give thetitle compound contaminated by impurities as a white solid (59 mg). Thefiltrate was dried over sodium sulphate, filtered and concentrated invacuo to give a yellow solid (143 mg). The crude was purified bypreparative TLC (eluent: dichloromethane/MeOH 93/7) to give the titlecompound (10 mg, 4%) as a white solid.

LCMS (ESI+) m/z 257/259 (M+H)⁺: 100%.

Step 3:3-(Hydroxymethyl)-6-[(1E)-3-{4-[(4-fluorophenoxy)methyl]piperidin-1-yl}-3-oxoprop-1-en-1-yl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one

To a suspension of6-bromo-3-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one (10 mg,0.039 mmol; which may be prepared as described in Step 2) in DMF (200μL) and proprionitrile (200 μL) under Argon were added DIPEA (8 μL,0.047 mmol), 1-acryloyl-4-[(4-fluorophenoxy)methyl]piperidine (14 mg,0.053 mmol; which may be prepared as described in Step 1),tri(o-tolyl)phosphine (2 mg, 0.008 mmol) and palladium acetate (1 mg,0.004 mmol). The mixture was stirred at 100° C. for 2 days, then wasallowed to come back to room temperature, filtered through Celite pad.The residue obtained after concentration of the filtrate was purified bypreparative TLC (eluent: DCM/MeOH 9/1) to give the title compound as awhite solid (1 mg, 6%).

LCMS (ESI+) m/z 440 (M+H)⁺: 100%.

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 8.31 (s, 1H), 8.20 (br s, 1H),7.70-7.58 (m, 2H), 6.99-6.80 (m, 5H), 4.84-4.72 (m, 1H), 4.22-4.10 (m,1H), 4.03-3.87 (m, 2H), 3.85-3.72 (m, 2H), 3.25-3.13 (m, 1H), 3.03-2.61(m, 5H), 2.15-1.87 (m, 3H), 1.44-1.31 (m, 2H).

Example 29(E)-6-(3-Oxo-3-(3-(2-(thiophen-2-yl)ethoxy)azetidin-1-yl)prop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E29) Step 1: 1-Benzhydrylazetidin-3-yl methanesulfonate

Triethylamine (870 ml, 62.67 mmol) and mesyl chloride (390 μL, 50.13mmol) were successively added to a solution of 1-benzhydrylazetan-3-ol(1.0 g, 41.78 mmol) in dichloromethane (10 mL) at room temperature. Thereaction mixture was stirred for 1 hour and then diluted by addition ofwater (20 mL). The aqueous phase was separated and extracted withdichloromethane (2×40 mL). The combined organic phases were washed witha saturated solution of sodium chloride (40 mL), dried over sodiumsulfate, filtered and concentrated to dryness. The title compound wasobtained as a yellow solid (1.5 g, 100%).

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 7.41-7.19 (m, 10H), 5.12 (q, J=6 Hz,1H), 4.41 (s, 1H), 3.68-3.66 (m, 2H), 3.23-2.21 (m, 2H), 2.99 (s, 3H).

Step 2: 1-Benzhydryl-3-(2-(thiophen-2-yl)ethoxy)azetidine

A solution of 1-benzhydrylazetidin-3-yl methanesulfonate (324 mg, 1.0mmol) in thiophene ethanol (2.3 mL, 20.4 mmol) was stirred undermicrowave irradiations (100 W) at 110° C. for 30 minutes. The reactionmixture was then partitioned between dichloromethane (20 mL) and asolution of sodium hydroxyde (1N, 10 mL). The aqueous layer wasseparated and extracted with dichloromethane (2×10 mL). The combinedorganic phases were dried over sodium sulfate, filtered and concentratedto dryness. The residue was purified by chromatography on silica gel,using petroleum ether/ethyl acetate (85:15) as eluent. The title productwas obtained as a yellow solid (210 mg, 59%).

LCMS (ESI-APCI) m/z 350.2 (M+H)⁺

Step 3: 3-(2-(Thiophen-2-yl)ethoxy)azetidine hydrochloride hydrochloride

1-Chloroethylchloroformate (361 μL, 3.33 mmol) was added to a solutionof 1-benzhydryl-3-(2-(thiophen-2-yl)ethoxy)azetidine (1.11 g, 3.17 mmol)in dichloromethane (15 mL) at room temperature. The reaction mixture wasstirred overnight at room temperature, then 1 hour at 70° C. Aftercooling down to room temperature, ethanol (15 mL) was added and thereaction mixture was stirred at 70° C. for 1 hour. After concentrationto dryness, the crude mixture was triturated in pentane (2×15 mL) togive a yellow oil (698 mg, quantitative) which was used in the next stepwithout further purification.

LCMS (ESI-APCI) m/z 184.2 (M+H)⁺

Step 4:(E)-6-(3-Oxo-3-(3-(2-(thiophen-2-yl)ethoxy)azetidin-1-yl)prop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one

3-(2-(Thiophen-2-yl)ethoxy)azetidine hydrochloride (128 mg, 0.6 mmol),EDCI (113 mg, 0.6 mmol), HOBt (80 mg, 0.6 mmol) anddiisopropylethylamine (170 μL, 1.0 mmol) were successively added to asolution of(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acidhydrochloride (100 mg, 0.4 mmol) in dimethylformamide (10 mL) at roomtemperature. The reaction mixture was stirred overnight and thenpartitioned between ethyl acetate (40 mL) and water (20 mL). The aqueouslayer was separated and extracted with ethyl acetate (2×20 mL). Thecombined organic phases were washed with a saturated solution of sodiumchloride (3×30 mL), dried over sodium sulfate and concentrated todryness. The residue was purified by chromatography on silica gel, usingdichloromethane/methanol (99:1 to 95:5) as eluent. The residue wastriturated with acetone to give a white solid (40 mg, 27%).

LCMS (ESI-APCI) 384.1 m/z (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 10.68 (s, NH), 8.34 (s, 1H), 8.01(s, 1H), 7.4 (d, J=15.6 Hz, 1H), 7.36-7.33 (m, 1H), 6.97-6.82 (m, 2H),6.72 (d, J=15.6 Hz, 1H), 4.50-4.38 (m, 2H), 4.14-4.03 (m, 2H), 3.77-3.70(m, 1H), 3.63-3.59 (m, 2H), 3.07 (t, J=6.2 Hz, 2H), 2.91 (t, J=7.6 Hz,2H), 2.5 (t, J=7.6 Hz, 2H). The CH₂ at 2.5 ppm is partially hidden byDMSO.

Example 30(E)-6-(3-Oxo-3-(3-(3-(thiophen-2-yl)propoxy)azetidin-1-yl)prop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E30) Step 1: 3-(2-Thienyl)propanol

Borane methylsulfide complex (6.4 mL, 12.8 mmol) was added to a solutionof 3-(2-thienyl)propanoic acid (1.0 g, 6.4 mmol) in THF (18 mL) at 0° C.The reaction mixture was stirred at 0° C. for 2 hours and at roomtemperature for 3 additional hours. After cooling down to 0° C., thereaction was quenched by addition of a saturated solution of potassiumcarbonate (5 mL). The aqueous layer was separated and extracted withethyl acetate (2×15 mL) and diethyl ether (2×15 mL). The combinedorganic phases were dried over sodium sulfate, filtered and concentratedto dryness. The title compound was obtained as a colorless oil (1.0 g,100%).

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 7.18-7.17 (m, 1H), 6.99-6.96 (m, 1H),6.87-6.86 (m, 1H), 3.79-3.74 (m, 2H), 3.0 (t, J=7.6 Hz, 2H), 2.4-1.97(m, 2H).

Step 2: 2-(3-Chloropropyl)thiophene

Thionyl chloride (420 μL, 5.7 mmol) was added to a solution of3-(2-thienyl)propanol (682.0 mg, 4.8 mmol) in THF (3 mL) at roomtemperature. The reaction mixture was stirred at 50° C. for 2 hours andthen concentrated to dryness to afford the title compound as a brownoil. The product was used in the next step without further purification.

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 7.34-7.32 (m, 1H), 6.96-6.94 (m,1H), 6.89-6.88 (m, 1H), 3.69-3.63 (m, 2H), 2.84 (t, J=7.6 Hz, 2H),2.08-2.01 (m, 2H).

Step 3: 1-Benzhydryl-3-(3-(thiophen-2-yl)propoxy)azetidine

Sodium hydride (60% in oil, 200.0 mg, 5 mmol) was added to a solution of1-benzhydryl-3-azetidin-3-ol (500.0 mg, 2.1 mmol) in dimethylformamide(3 mL) at room temperature. The mixture was stirred for 30 minutes priorto the addition of 2-(3-chloropropyl)thiophene (772.0 mg, 4.8 mmol) insolution in dimethylformamide (2 mL). The reaction mixture was stirredat 80° C. overnight then concentrated to dryness. The residue waspartitioned between ethyl acetate (30 mL) and water (30 mL). The aqueouslayer was separated and extracted with ethyl acetate (2×15 mL). Thecombined organic phases were washed with a saturated solution of sodiumchloride (3×30 mL), dried over sodium sulfate, filtered and concentratedto dryness. The residue was purified by chromatography on silica gel,using petroleum ether/ethyl acetate (99:1 to 90:10) as eluent. The titleproduct was obtained as a yellow oil (320 mg, 42%).

LCMS (ESI-APCI) m/z 364.2 (M+H)⁺

Step 4: 3-(4-Methyl-thiophen-2-ylmethoxy)-azetidine hydrochloride

1-Chloroethyl chloroformate (65.5 μL, 21.5 mmol) was added to a solutionof 1-benzhydryl-3-(3-(thiophen-2-yl)propoxy)azetidine (220 mg, 0.61mmol) in dichloromethane (7 mL) at 0° C. The reaction mixture wasstirred 2 hours at 0° C. and then allowed to warm up to roomtemperature. Ethanol (9 mL) was added and the reaction mixture wasstirred for 2 additional hours at room temperature. After concentrationto dryness, the crude mixture was triturated in pentane (2×15 mL) togive a brown solid (140 mg, quantitative) which was used in the nextstep without further purification.

LCMS (ESI-APCI) m/z 198.2 (M+H)⁺

Step 5:(E)-6-(3-Oxo-3-(3-(3-(thiophen-2-yl)propoxy)azetidin-1-yl)prop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one

3-(4-Methyl-thiophen-2-ylmethoxy)-azetidine hydrochloride (128.0 mg, 0.6mmol), EDCI (113. mg, 0.6 mmol), HOBt (80.0 mg, 0.6 mmol) anddiisopropylethylamine (170 μL, 1.0 mmol) were successively added to asolution of(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acidhydrochloride (100.0 mg, 0.4 mmol) in dimethylformamide (10 mL) at roomtemperature. The reaction mixture was stirred overnight and thenpartitioned between ethyl acetate (30 mL) and water (30 mL). The aqueouslayer was separated and extracted with ethyl acetate (2×20 mL). Thecombined organic phases were washed with a saturated solution of sodiumchloride (3×30 mL), dried over sodium sulfate, filtered and concentratedto dryness. The residue was purified by chromatography on silica gelusing dichloromethane/methanol (99:1 to 95:5) as eluent. The residue wastriturated in acetone to give the title compound as a white solid (40.0mg, 27%).

LCMS (ESI-APCI) 398.1 m/z (M+H)⁺

¹NMR (DMSO-d₆, 400 MHz): δ (ppm): 10.69 (br s, NH), 8.34 (s, 1H), 8.02(s, 1H), 7.40 (d, J=15.6 Hz, 1H), 7.34-7.31 (m, 1H), 6.96-6.94 (m, 1H),6.88-6.87 (m, 1H), 6.72 (d, J=15.6 Hz, 1H), 4.49-4.47 (m, 1H), 4.45 (m,1H), 4.34-4.06 (m, 2H), 3.76-3.72 (m, 1H), 3.42 (t, J=7.6 Hz, 2H),2.92-2.85 (m, 4H), 2.55 (t, J=7.6 Hz, 2H), 1.9-1.83 (m, 2H). The CH₂ at2.5 ppm is partially hidden by DMSO.

Example 31(E)-6-(3-(3-((3-Methylthiophen-2-yl)methoxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E31) Step 1: (3-Methylthiophen-2-yl)methanol

Sodium borohydride (718 mg, 19.02 mmol) was added portionwise, at 0° C.,to a solution of 3-methylthiophene-2-carbaldehyde (2.0 g, 15.85 mmol) ina mixture of ethanol and toluene (1:1, 12 mL). The reaction mixture wasstirred 2 hours at room temperature and then partitioned between ethylacetate (15 mL) and water (15 mL). The aqueous layer was separated andextracted with ethyl acetate (3×45 mL). The combined organic phases werewashed with a saturated solution of sodium chloride (1×10 mL), driedover sodium sulfate, filtered and concentrated under vacuum to give thetitle product as a pink oil (2.24 g, 99%).

¹NMR (CDCl₃, 400 MHz): δ (ppm): 7.16 (d, J=5.2 Hz, 1H), 6.84 (d, J=5.2Hz, 1H), 4.76 (s, 2H), 2.23 (s, 3H).

Step 2: 2-(Chloromethyl)-3-methylthiophene

Thionyl chloride (430 μL, 5.8 mmol) was added at 0° C. to a solution of(3-methylthiophen-2-yl)methanol (624 mg, 4.8 mmol) in tetrahydrofuran (3mL). The reaction mixture was stirred 2 hours at 50° C. thenconcentrated to dryness. The title compound was used in the next stepwithout further purification.

Step 3: 1-Benzhydryl-3-((3-methylthiophen-2-yl)methoxy)azetidine

Sodium hydride (60% in oil, 106 mg, 2.3 mmol) was added to a solution of1-benzhydryl-3-azetidin-3-ol (580 mg, 2.0 mmol) in dimethylformamide (3mL) at room temperature. The reaction mixture was stirred at roomtemperature for 30 minutes prior to the addition of2-(chloromethyl)-3-methylthiophene (714 mg, 4.8 mmol) in solution indimethylformamide (2 mL). The reaction mixture was stirred at 80° C.overnight and cooled to room temperature. The mixture was thenpartitioned between ethyl acetate (30 mL) and water (30 mL). The aqueouslayer was separated and extracted with ethyl acetate (3×20 mL). Thecombined organic phases were washed with a saturated solution of sodiumchloride (3×30 mL), dried over sodium sulfate, filtered and concentratedto dryness. The residue was purified by chromatography on silica gel,using petroleum ether/ethyl acetate (95:5 to 9:1) as eluent. The titleproduct was obtained as a yellow oil (267 mg, 36%).

LCMS (ESI-APCI) m/z 350.2 (M+H)⁺

Step 4: 3-((3-Methylthiophen-2-yl)methoxy)azetidine hydrochloride

1-Chloroethyl chloroformate (90 μL, 0.84 mmol) was added to a solutionof 1-benzhydryl-3-((3-methylthiophen-2-yl)methoxy)azetidine (290 mg,0.83 mmol) in dichloromethane (9 mL) at 0° C. The reaction mixture wasstirred 3 hours, then 30 minutes at room temperature. Ethanol (9 mL) wasadded and the reaction mixture was stirred at 35° C. for an additional 3hours. After concentration to dryness, the crude was triturated inpentane to give a yellow solid (200 mg, quantitative) which was used inthe next step without further purification.

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 9.79 (s, 1H), 9.50 (s, 1H), 7.19 (d,J=5.6 Hz, 1H), 6.82 (d, J=5.6 Hz, 1H), 4.57 (s, 2H), 4.50-4.46 (m, 1H),4.06-4.01 (m, 2H), 3.94-3.89 (m, 2H), 2.23 (s, 3H).

Step 5:(E)-6-(3-(3-((3-Methylthiophen-2-yl)methoxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one

3-((3-methylthiophen-2-yl)methoxy)azetidine hydrochloride (129.0 mg, 0.6mmol), EDCI (112.0 mg, 0.6 mmol), HOBt (82.0 mg, 0.6 mmol) anddiisopropylethylamine (170 μL, 1.0 mmol) were successively added to asolution of(E)-3-(7-Oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acidhydrochloride (100.0 mg, 0.4 mmol) in dimethylformamide (10 mL) at roomtemperature. The reaction mixture was stirred overnight and thenpartitioned between ethyl acetate (30 mL) and water (30 mL). The aqueouslayer was separated and extracted with ethyl acetate (2×20 mL). Thecombined organic phases were washed with a saturated solution of sodiumchloride (3×30 mL), dried over sodium sulfate, filtered and concentratedto dryness. The residue was purified by chromatography on silica gel,using dichloromethane/methanol (100:0 to 95:5) as eluent. The residuewas triturated in acetone to give a white solid (66.0 mg, 44%).

LCMS (ESI-APCI) m/z 384.2 (M+H)⁺

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 8.67 (br s, NH), 8.32 (s, 1H), 7.63(s, 1H), 7.57 (d, J=15.6 Hz, 1H), 7.21 (d, J=4.8 Hz, 1H), 6.85 (d, J=4.8Hz, 1H), 6.39 (d, J=15.6 Hz, 1H), 4.62-4.61 (m, 2H), 4.46-4.40 (m, 2H),4.28-4.23 (m, 1H), 4.16-4.14 (m, 1H), 4.01-3.98 (m, 1H), 2.99 (t, J=8Hz, 2H), 2.69 (t, J=8 Hz, 2H), 2.25 (s, 3H).

Example 326-[3-(3-(4-Methyl-thiophen-2ylmethoxy)-azetidin-1-yl)-3-oxo-propenyl]-3,4-dihydro-1H-[1,8]naphthyridin-2-one(E32) Step 1: (4-Methyl-thiophen-2-yl)methanol

Sodium borohydride (719.0 mg, 19 mmol) was added to a solution of4-methyl-thiophene-2-carbaldehyde (2.0 g, 15.8 mmol) in a mixture ofethanol and toluene (1:1, 12 mL) at 0° C. The reaction mixture wasstirred for 2 hours at room temperature and then directly partitionedbetween water (10 mL) and ethyl acetate (15 mL). The aqueous layer wasseparated and extracted with ethyl acetate (2×20 mL). The combinedorganic phases were washed with a saturated solution of sodium chloride,dried over sodium sulfate, filtered and concentrated to dryness. Thetitle product was obtained as a yellow oil (2.1 g, 95%).

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 6.85 (s, 1H), 6.83 (s, 1H), 4.76 (d,J=5.6 Hz, 2H), 2.34 (s, 3H), 1.81 (t, J=6 Hz, OH).

Step 2: 2-Chloromethyl-4-methyl-thiophene

Thionyl chloride (1.3 mL, 17.7 mmol) was added to a solution of(4-methyl-thiophen-2-yl)methanol (1.9 g, 14.8 mmol) in tetrahydrofuran(7 mL) at 0° C. The reaction mixture was stirred at 50° C. for 2 hoursthen concentrated to dryness. The title product was obtained as a brownoil (2.17 g, quantitative) which was used in the next step withoutfurther purification.

Step 3: 1-Benzhydryl-3-(4-methyl-thiophen-2-ylmethoxy)-azetidine

Sodium hydride (60% in oil, 88.0 mg, 2.3 mmol) was added to a solutionof 1-benzhydryl-3-azetidin-3-ol (500 mg, 2.0 mmol) in dimethylformamide(3 mL) at room temperature. The reaction mixture was stirred for 30minutes prior to the addition of 2-chloromethyl-4-methyl-thiophene (714mg, 4.8 mmol) in solution in dimethylformamide (2 mL). The reactionmixture was stirred at 80° C. overnight and cooled to room temperature.The mixture was then partitioned between ethyl acetate (30 ml) and water(30 mL). The aqueous layer was separated and extracted with ethylacetate (2×30 mL). The combined organic phases were washed with asaturated solution of sodium chloride (3×30 mL), dried over sodiumsulfate, filtered and concentrated to dryness. The residue was purifiedby chromatography on silica gel, using petroleum ether/ethyl acetate(95:5 to 90:10) as eluent. The title product was obtained as a yellowsolid (400 mg, 55%).

LCMS (ESI-APCI) m/z 350.2 (M+H)⁺

Step 4: 3-(4-Methyl-thiophen-2-ylmethoxy)-azetidine hydrochloride

1-Chloroethyl chloroformate (50.0 μL, 0.4 mmol) was added to a solutionof 1-benzhydryl-3-(4-methylthiophen-2-ylmethoxy)-azetidine (150.0 mg,0.4 mmol) in dichloromethane (4.5 mL) at 0° C. The reaction mixture wasstirred 3 hours, then 30 minutes at room temperature. Ethanol (6 mL) wasadded and the reaction mixture was stirred at 35° C. for an additional 4hours. After concentration to dryness, the crude was triturated inpentane (2×10 mL) to give a yellow solid (94.0 mg, quantitative) whichwas used in the next step without further purification.

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 8.99 (br s, NH₂), 7.12 (s, 1H), 6.92(s, 1H), 4.61 (s, 2H), 4.45-4.42 (m, 1H), 4.11-4.05 (m, 2H), 3.78-3.75(m, 2H), 2.19 (s, 3H).

Step 5:6-[3-(3-(4-Methyl-thiophen-2ylmethoxy)-azetidin-1-yl)-3-oxo-propenyl]-3,4-dihydro-1H-[1,8]naphthyridin-2-one

3-(4-methyl-thiophen-2-ylmethoxy)-azetidine hydrochloride (128.0 mg, 0.6mmol), EDCI (113.0 mg, 0.6 mmol), HOBt (80.0 mg, 0.6 mmol) anddiisopropylethylamine (170 μL, 1.0 mmol) were successively added to asolution of(E)-3-(7-Oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acidhydrochloride (100.0 mg, 0.4 mmol) in dimethylformamide (10 mL) at roomtemperature. The reaction mixture was stirred at room temperatureovernight and then partitioned between ethyl acetate (20 mL) and water(20 mL). The aqueous layer was separated and extracted with ethylacetate (2×20 ml). The combined organic phases were washed with asaturated solution of sodium chloride (3×20 mL), dried over sodiumsulfate, filtered and concentrated to dryness. The residue was purifiedby chromatography on silica gel, using dichloromethane/methanol (99:1 to95:5) as eluent. The residue was triturated with acetone to give a whitesolid (40 mg, 27%).

LCMS (ESI-APCI) 384.2 m/z (M+H)⁺

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 8.39 (br s, NH), 8.30 (s, 1H), 7.64(s, 1H), 7.57 (d, J=15.6 Hz, 1H), 6.90 (s, 1H), 6.84 (s, 1H), 6.39 (d,J=15.6 Hz, 1H), 4.62 (s, 2H), 4.47-4.39 (m, 2H), 4.28-4.24 (m, 1H),4.18-4.15 (m, 1H), 4.02-3.99 (m, 1H), 3.00 (t, J=7.2 Hz, 2H), 2.70 (t,J=7.6 Hz, 2H), 2.24 (s, 3H).

Example 33(E)-6-(3-(3-((5-Methylthiophen-2-yl)methoxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E33) Step 1: (5-Methyl-thiophen-2-yl)-methanol

Sodium borohydride (720 mg, 19.02 mmol) was added to a solution of5-methyl-thiophene-2-carbaldehyde (2.0 g, 15.85 mmol) in a mixture ofethanol and toluene (1:1, 12 mL) at 0° C. The reaction mixture wasstirred 2 hours at room temperature and then partitioned between water(15 mL) and ethyl acetate (15 mL). The aqueous layer was separated andextracted with ethyl acetate (2×30 mL). The combined organic phases werewashed with a saturated solution of sodium chloride (20 mL), dried oversodium sulfate, filtered and concentrated to dryness. The title productwas obtained as a yellow oil (2.01 g, 99%).

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 6.79 (d, J=2.8 Hz, 1H), 6.61 (d, J=2.8Hz, 1H), 4.73 (s, 2H), 2.47 (s, 3H).

Step 2: 2-(Chloromethyl)-5-methylthiophene

Triethylamine (2.2 mL, 16.0 mmol) and a solution of thionyl chloride(1.3 mL, 17.7 mmol) in dichloromethane (20 mL) were successively addedto a solution of (5-methyl-thiophen-2-yl)-methanol (1.9 g, 14.6 mmol) indichloromethane (20 mL) at 0° C. The reaction mixture was stirred 2hours at reflux then cooled to room temperature. The mixture was thenpartitioned between water (15 mL) and ethyl acetate (20 mL). The organicphase was separated, dried over sodium sulfate, filtered andconcentrated to dryness. The residue was purified by chromatography onsilica gel, using petroleum ether/ethyl acetate (10:0 to 9:1) as eluent.The title product was obtained as a brown oil (1.5 g, 71%).

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 6.87 (d, J=3.2 Hz, 1H), 6.59 (d, J=3.2Hz, 1H), 4.75 (s, 2H), 2.47 (s, 3H).

Step 3: 1-Benzhydryl-((5-methylthiophen-2-yl)methoxy)-azetidine

Sodium hydride (60% in oil, 204.0 mg, 5.1 mmol) was added to a solutionof 1-benzhydryl-3-azetidin-3-ol (816.0 mg, 3.4 mmol) indimethylformamide (10 mL) at room temperature. The reaction mixture wasstirred for 30 minutes prior to the addition of2-(chloromethyl)-5-methylthiophene (1.5 g, 10.2 mmol) in solution indimethylformamide (5 mL). The reaction mixture was stirred at 50° C. for60 hours and cooled to room temperature. The reaction mixture was thenpartionned between ethyl acetate (20 mL) and water (20 mL). The aqueouslayer was separated and extracted with ethyl acetate (2×20 mL). Thecombined organic phases were washed with a saturated solution of sodiumchloride (3×30 mL). The organic phase was dried over sodium sulfate,filtered and concentrated to dryness. The residue was purified bychromatography on silica gel, using petroleum ether/ethyl acetate(90:10) as eluent. The title product was obtained as a yellow solid(580.0 mg, 49%).

LCMS (ESI-APCI) m/z 350.2 (M+H)⁺

Step 4: 3-((5-Methylthiophen-2-yl)methoxy)-azetidine hydrochloride

1-Chloroethyl chloroformate (198 μL, 1.8 mmol) was added to a solutionof 1-benzhydryl-((5-methylthiophen-2-yl)methoxy)-azetidine (580.0 mg,1.6 mmol) in dichloromethane (10 mL) at 0° C. The reaction mixture wasstirred for 1 h30 at the same temperature and 30 minutes at roomtemperature. Methanol (10 mL) was then added and the reaction mixturewas stirred for an additional 3 hours at 35° C. After concentration todryness, the crude was triturated in petroleum ether (10 mL) and diethylether (10 mL) to give a yellow oil (190 mg, 52%) which was used in thenext step without further purification.

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 8.87 (br s, NH₂), 6.89 (d, J=2.8 Hz,1H), 6.69 (d, J=2.8 Hz, 1H), 4.57 (s, 2H), 4.44-4.40 (m, 1H), 4.07-4.04(m, 2H), 3.78-3.75 (m, 2H), 2.43 (s, 3H).

Step 5:(E)-6-(3-(3-((5-Methylthiophen-2-yl)methoxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one

3-((5-Methylthiophen-2-yl)methoxy)-azetidine hydrochloride (190.0 mg,0.9 mmol), EDCI (190.0 mg, 1.0 mmol), HOBt (137 mg, 1.0 mmol) anddiisopropylethylamine (287 μL, 1.6 mmol) were successively added to asolution of(E)-3-(7-Oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acidhydrochloride (168.0 mg, 0.7 mmol) in dimethylformamide (15 mL) at roomtemperature. The reaction mixture was stirred overnight and thenpartionned between ethyl acetate (30 mL) and water (30 mL). The aqueouslayer was separated and extracted with ethyl acetate (2×30 ml). Thecombined organic phases were washed with a saturated solution of sodiumchloride (3×30 mL), dried over sodium sulfate, filtered and concentratedto dryness. The residue was purified by chromatography on silica gel,using dichloromethane/methanol (98:2 to 95:5) as eluent. The residue wastriturated in diethyl ether to give a yellow solid (74.0 mg, 30%).

LCMS (ESI-APCI) 384.1 m/z (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 10.68 (br s, NH), 8.33 (s, 1H), 8.01(s, 1H), 7.39 (d, J=15.6 Hz, 1H), 6.89 (d, J=3.2 Hz, 1H), 6.7 (d, J=15.6Hz, 1H), 6.69 (d, J=3.2 Hz, 1H), 4.57 (s, 2H), 4.46-4.41 (m, 2H),4.12-4.06 (m, 2H), 3.73-3.69 (m, 1H), 2.89 (t, J=8 Hz, 2H), 2.50 (t, J=8Hz, 2H), 2.43 (s, 3H). The CH₂ at 2.5 ppm is partially hidden by DMSO.

Example 34(E)-6-[3-(2-Methoxyethoxyl)azetidin-1-yl)-3-oxoprop-1-enyl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E34) Step 1: 1-Benzhydryl-3-(2-methoxyethoxy)-azetidine

Sodium hydride (60% in oil, 55.0 mg, 1.4 mmol) was added to a solutionof 1-benzhydryl-3-azetidin-3-ol (300 mg, 1.2 mmol) in dimethylformamide(2.6 mL) at room temperature. The reaction mixture was stirred for 30minutes prior to the addition of 1-bromo-2-methoxyethane (1.5 mL, 1.9mmol). The reaction mixture was stirred overnight and then directlypartitioned between dichloromethane (20 mL) and water (20 mL). Theaqueous phase was separated and extracted with dichloromethane (2×30mL). The combined organic layer were washed with a saturated solution ofsodium chloride (3×30 mL), dried over sodium sulfate, filtered andconcentrated to dryness. The residue was purified by chromatography onsilica gel, using pentane/ethyl acetate (98:2 to 80:20) as eluent. Thetitle product was obtained as an orange oil (230 mg, 62%).

LCMS (ESI-APCI) m/z 298.0 (M+H)⁺.

Step 2: 3-(2-Methoxyethoxy)-azetidine hydrochloride

1-Chloroethyl chloroformate (102 μL, 0.9 mmol) was added to a solutionof 1-benzhydryl-3-(2-methoxyethoxy)-azetidine (215 mg, 0.7 mmol) in1,2-dichloroethane (3 mL) at room temperature. The reaction mixture wasthen heated up to 70° C. and stirred for 2.5 hours. After cooling downto room temperature, methanol (3 mL) was added and the reaction mixturewas stirred overnight at 70° C. The mixture was then concentrated todryness and the residue was triturated in pentane (2×15 mL) to give ayellow oil (109 mg, 90%) which was used in the next step without furtherpurification.

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 9.69 and 9.45 (br s, NH₂), 4.43-4.41(m, 1H), 4.13-4.10 (m, 2H), 3.97-3.94 (m, 2H), 3.52-3.50 (m, 2H),3.42-3.40 (m, 2H), 3.28 (s, 3H).

Step 3:(E)-6-[3-(2-Methoxyethoxyl)azetidin-1-yl)-3-oxoprop-1-enyl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one

3-(2-Methoxyethoxy)-azetidine hydrochloride (98 mg, 0.6 mmol), EDCI (117mg, 0.6 mmol), HOBt (82 mg, 0.6 mmol) and diisopropylethylamine (170 μL,1.0 mmol) were successively added to a solution of(E)-3-(7-Oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acidhydrochloride (100.0 mg, 0.4 mmol) in dimethylformamide (10 mL) at roomtemperature. The reaction mixture was stirred overnight and thenpartitioned between ethyl acetate (30 mL) and water (30 mL). The aqueouslayer was separated and successively extracted with ethyl acetate (2×30mL) and dichloromethane (2×20 mL). The combined organic phases werewashed with a saturated solution of sodium chloride (3×20 mL), driedover sodium sulfate, filtered and concentrated to dryness. The residuewas purified by chromatography on silica gel, usingdichloromethane/methanol (98:2 to 95:5) as eluent. After precipitationin a mixture of dichloromethane and diethyl ether, the title product wasobtained as a yellow solid (70 mg, 54%).

LCMS (ESI-APCI) m/z 332.0 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 10.65 (br s, NH), 8.35 (s, 1H), 8.01(s, 1H), 7.40 (d, J=15.6 Hz, 1H),), 6.72 (d, J=15.6 Hz, 1H), 4.49-4.45(m, 1H), 4.38-4.35 (m, 1H), 4.15-4.06 (m, 2H), 3.75-3.72 (m, 1H),3.72-3.46 (m, 4H), 3.27 (s, 3H), 2.92 (t, J=7.2 Hz, 2H), 2.54 (t, J=7.2Hz, 2H). The triplet CH₂ at 2.54 ppm is partially hidden by DMSO.

Example 35(E)-6-[3-(3-Methoxypropoxyl)azetidin-1-yl)-3-oxoprop-1-enyl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E35) Step 1: 1-Benzhydryl-3-(3-methoxypropoxy)-azetidine

Sodium hydride (60% in oil, 92 mg, 2.3 mmol) was added to a solution of1-benzhydryl-3-azetidin-3-ol (500 mg, 2.1 mmol) in dimethylformamide (2mL) at room temperature. The reaction mixture was stirred for 30 minutesprior to the addition of 1-chloro-3-methoxypropane (520 μL, 4.8 mmol) insolution in dimethylformamide (3 mL). The mixture was then stirred at80° C. overnight. Since the conversion was still incomplete, sodiumhydride (60% in oil, 42 mg, 1.1 mmol) and 1-chloro-3-methoxypropane (111μL, 1.1 mmol) were added a second time. The reaction mixture was thenstirred at 80° C. for one extra night. The mixture was then directlypartitioned between ethyl acetate (30 mL) and water (30 mL). The aqueouslayer was separated and extracted with ethyl acetate (2×30 mL). Thecombined organic phases were washed with a saturated solution of sodiumchloride (3×30 mL), dried over sodium sulfate, filtered and concentratedto dryness. The residue was purified by chromatography on silica gel,using petroleum ether/ethyl acetate (8:2) as eluent. The title productwas obtained as a white solid (460 mg, 71%).

LCMS (ESI-APCI) m/z 312.0 (M+H)⁺

Step 2: 3-(3-Methoxypropoxy)-azetidine hydrochloride

1-Chloroethyl chloroformate (210 μL, 1.9 mmol) was added to a solutionof 1-benzhydryl-3-(3-methoxypropoxy)-azetidine (460 mg, 1.5 mmol) in1,2-dichloroethane (7 mL) at room temperature. The reaction mixture wasthen heated up to 70° C. and stirred for 1.5 hours. After cooling downto room temperature, methanol (7 mL) was added and the mixture was againwarmed up to 70° C. and stirred for an additional 2 hours. Afterconcentration to dryness, the crude was triturated in pentane (2×10 mL)to afford a yellow oil (247 mg, 92%) which was used in the next stepwithout further purification.

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 9.00 (br s, NH₂), 4.33-4.30 (m, 1H),4.13-4.10 (m, 2H), 3.79-3.75 (m, 2H), 3.42-3.35 (m, 4H), 3.22 (s, 3H),1.74-1.72 (m, 2H).

Step 3:(E)-6-[3-(3-methoxypropoxyl)azetidin-1-yl)-3-oxoprop-1-enyl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one

3-(3-Methoxypropoxy)-azetidine hydrochloride (107 mg, 0.6 mmol), EDCI(117 mg, 0.6 mmol), HOBt (82 mg, 0.6 mmol) and diisopropylethylamine(170 μL, 1.0 mmol) were successively added to a solution of(E)-3-(7-Oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acidhydrochloride (100 mg, 0.4 mmol) in dimethylformamide (10 mL) at roomtemperature. The reaction mixture was stirred over the week-end thenpartitioned between ethyl acetate (30 mL) and water (30 mL). The aqueouslayer was separated and successively extracted with ethyl acetate (2×30mL) and dichloromethane (2×30 mL). The combined organic phases werewashed with a saturated solution of sodium chloride (3×20 mL), driedover sodium sulfate, filtered and concentrated to dryness. The residuewas purified by chromatography on silica gel, usingdichloromethane/methanol (98:2 to 95:5) as eluent. The title product wasobtained as a yellow solid (98 mg, 72%).

LCMS (ESI-APCI) m/z 346.2 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 10.64 (br s, NH), 8.34 (s, 1H), 8.00(s, 1H), 7.39 (d, J=14.8 Hz, 1H), 6.71 (d, J=16 Hz, 1H), 4.48-4.44 (m,1H), 4.35-4.30 (m, 1H), 4.14-4.05 (m, 2H), 3.71 (d, J=10.8 Hz, 1H),3.43-3.39 (m, 4H), 3.22 (s, 3H), 2.90 (t, J=7.6 Hz, 2H), 2.55-2.50 (t,J=7.6 Hz, 2H), 1.77-1.74 (m, 2H). The multiplet CH₂ at 2.5 ppm ispartially hidden by DMSO.

Example 36(E)-6-[3-(3-Butoxyazetidin-1-yl)-3-oxoprop-1-enyl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E36) Step 1: 1-Benzhydryl-3-butoxyazetidine

Sodium hydride (60% in oil, 92 mg, 2.3 mmol) was added to a solution of1-benzhydryl-3-azetidin-3-ol (500 mg, 2.1 mmol) in dimethylformamide (3mL) at room temperature. The resulting mixture was stirred for 30minutes prior to the addition of 1-chlorobutane (500 μL, 4.8 mmol) insolution in dimethylformamide (3 mL). The reaction mixture was thenstirred at 80° C. overnight and cooled to room temperature prior to theaddition of ethyl acetate (20 mL) and water (20 mL). The aqueous layerwas separated and extracted with ethyl acetate (2×30 mL). The combinedorganic phases were washed twice with a saturated solution of sodiumchloride (2×100 mL). The organic phase was dried over sodium sulfate,filtered and concentrated to dryness. The residue was purified bychromatography on silica gel, using petroleum ether/ethyl acetate (95:5)as eluent. The title product was obtained as a white solid (370 mg,60%).

LCMS (ESI-APCI) m/z 296.0 (M+H)⁺

Step 2: 3-Butoxyazetidine hydrochloride

1-Chloroethyl chloroformate (180 μL, 1.6 mmol) was added to a solutionof 1-benzhydryl-3-butoxyazetidine (370 mg, 1.2 mmol) in1,2-dichloroethane (6 mL) at room temperature. The reaction mixture wasthen heated up to 70° C. and stirred for 1.5 hours. After cooling downto room temperature, methanol (7 mL) was added. The reaction mixture wasagain heated up to 70° C. and stirred for an additional 1.5 hours. Afterconcentration to dryness, the crude mixture was triturated in pentane(2×5 mL) to give a yellow oil (179 mg, 86%) which was used in the nextstep without further purification.

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 9.82 and 9.61 (br s, NH₂), 4.43-4.41(m, 1H), 4.19-4.15 (m, 2H), 4.01-3.98 (m, 2H), 3.37 (t, J=6.8 Hz, 2H),1.55-1.50 (m, 2H), 1.39-1.33 (m, 2H), 0.94-0.90 (m, 3H).

Step 3:(E)-6-[3-(3-Butoxyazetidin-1-yl)-3-oxoprop-1-enyl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one

3-Butoxyazetidine hydrochloride (100 mg, 0.6 mmol), EDCI (113 mg, 0.6mmol), HOBt (80 mg, 0.6 mmol) and diisopropylethylamine (170 μL, 1.0mmol) were successively added to a solution of(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acidhydrochloride (100 mg, 0.4 mmol) in dimethylformamide (10 mL) at roomtemperature. The reaction mixture was stirred overnight and thenpartioned between ethyl acetate (30 mL) and water (30 mL). The aqueouslayer was separated and extracted successively with ethyl acetate (2×20mL) and dichloromethane (2×20 mL). The combined organic phases werewashed with a saturated solution of sodium chloride (3×20 mL), driedover sodium sulfate, filtered and concentrated to dryness. The residuewas purified by chromatography on silica gel, usingdichloromethane/methanol (99:1 to 97:3) as eluent. The title product wasobtained as a grey solid (30 mg, 23%).

LCMS (ESI-APCI) m/z 330.2 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 10.64 (br s, NH), 8.33 (s, 1H), 8.00(s, 1H), 7.38 (d, J=16 Hz, 1H), 6.70 (d, J=15.6 Hz, 1H), 4.48-4.44 (m,1H), 4.34-4.30 (m, 1H), 4.15-4.05 (m, 2H), 3.73-3.68 (m, 1H), 3.38-3.35(m, 2H), 2.91 (t, J=8 Hz, 2H), 2.55-2.50 (t, J=8 Hz, 2H), 1.52-1.47 (m,2H), 1.37-1.31 (m, 2H), 0.89 (t, J=7.2 Hz, 3H). The CH₂ at 2.5 ppm ispartially hidden by DMSO.

Example 37(E)-6-[3-(3-Isobutoxyazetidin-1-yl)-3-oxoprop-1-enyl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E37) Step 1: 1-Benzhydryl-3-isobutoxyazetidine

Sodium hydride (60% in oil, 146 mg, 3.6 mmol) was added to a solution of1-benzhydryl-3-azetidin-3-ol (400 mg, 1.7 mmol) in dimethylformamide (2mL) at room temperature. The reaction mixture was stirred for 30 minutesprior to the addition of 1-chloro-2-methylpropane (820 μL, 7.8 mmol).The reaction mixture was stirred at 80° C. overnight and cooled to roomtemperature. The mixture was then immediately partitioned between ethylacetate (30 mL) and water (30 mL). The aqueous phase was separated andextracted with ethyl acetate (2×20 mL). The combined organic phases werewashed with a saturated solution of sodium chloride (3×20 mL), driedover sodium sulfate, filtered and concentrated to dryness. The residuewas purified by chromatography on silica gel, using petroleumether/ethyl acetate (99:1 to 9:1) as eluent. The title product wasobtained as a white solid (200 mg, 40%).

LCMS (ESI-APCI) m/z 296.0 (M+H)⁺

Step 2: 3-Isobutoxyazetidine hydrochloride

1-Chloroethyl chloroformate (83 μL, 0.77 mmol) was added to a solutionof 1-benzhydryl-3-isobutoxyazetidine (175 mg, 0.60 mmol) in1,2-dichloroethane (3 mL) at room temperature. The reaction mixture wasthen heated up to 70° C. and stirred for 1.5 hours. After cooling downto room temperature, methanol (3 mL) was added and the reaction mixturewas heated again to 70° C. and stirred for an additional 1.5 hours.After concentration to dryness, the crude mixture was triturated inpentane (2×5 mL) to give a yellow oil (98 mg, quantitative) which wasused in the next step without further purification.

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 9.78 and 9.61 (br s, NH₂), 4.42 (m,1H), 4.19-4.15 (m, 2H), 4.03-3.98 (m, 2H), 3.11 (d, J=6.4 Hz, 2H),1.83-1.79 (m, 1H), 0.88 (d, J=2 Hz, 6H).

Step 3:(E)-6-[3-(3-Isobutoxyazetidin-1-yl)-3-oxoprop-1-enyl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one

3-Isobutoxyazetidine hydrochloride (98 mg, 0.6 mmol), EDCI (113 mg, 0.6mmol), HOBt (80 mg, 0.6 mmol) and diisopropylethylamine (170 μL, 1.0mmol) were successively added to a solution of3-(chloromethyl)-1-methyl-1H-pyrazole (100 mg, 0.4 mmol) indimethylormamide (10 mL) at room temperature. The reaction mixture wasstirred over a week-end and then diluted by addition ethyl acetate (20mL) and water (2×20 mL). The aqueous layer was separated and extractedwith ethyl acetate (2×20 mL). The combined organic phases were washedwith a saturated solution of sodium chloride (3×20 mL), dried oversodium sulfate, filtered and concentrated to dryness. The residue waspurified by chromatography on silica gel, using dichloromethane/methanol(98:2 to 92:8) as eluent. The title product was obtained as a whitesolid (40 mg, 31%).

LCMS (ESI-APCI) m/z 330.2 (M+H)⁺

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 8.65 (br s, NH), 8.33 (s, 1H), 7.64(s, 1H), 7.58 (d, J=15.6 Hz, 1H), 6.43 (d, J=15.6 Hz, 1H), 4.46-4.43 (m,1H), 4.34-4.26 (m, 2H), 4.17-4.15 (m, 1H), 4.01-3.98 (m, 1H), 3.16-3.15(m, 2H), 3.00 (t, J=7.2 Hz, 2H), 2.70 (t, J=7.2 Hz, 2H), 1.89-1.83 (m,1H), 0.93 (d, J=6.8 Hz, 6H).

Example 38(E)-6-(3-(3-((1-Methyl-1H-pyrazol-3-yl)methoxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E38) Step 1: 3-(Chloromethyl)-1-methyl-1H-pyrazole

Thionyl chloride (274 μL, 3.75 mmol) was added to a solution of(1-methyl-1H-pyrazol-3-yl)methanol (350 mg, 3.13 mmol) in THF (2 mL) atroom temperature. The reaction mixture was then heated up to 50° C. andstirred for 2 hours. After cooling down to room temperature, the mixturewas concentrated to dryness. The title compound was used in the nextstep without further purification.

Step 2: 3-((1-Benzhydrylazetidin-3-yloxy)methyl-1H-pyrazole

Sodium hydride (60% in oil, 200 mg, 2.30 mmol) was added to a solutionof 1-benzhydryl-3-azetidin-3-ol (500 mg, 2.09 mmol) in dimethylformamide(3 mL) at room temperature. The reaction mixture was stirred for 30minutes prior to the addition of 3-(chloromethyl)-1-methyl-1H-pyrazole(523 mg, 3.13 mmol). The reaction mixture was then heated up to 80° C.and stirred overnight. Since the LCMS monitoring indicated the presenceof remained starting material, a second portion of sodium hydride (60%in oil, 200 mg, 2.30 mmol) was added. After an additional 8 hours at 80°C., the reaction mixture was partioned between ethyl acetate (30 mL) andwater (30 mL). The aqueous phase was separated and extracted with ethylacetate (2×20 mL). The combined organic phases were washed with brine(3×30 mL), dried over sodium sulfate, filtered and concentrated todryness. The residue was purified by chromatography on silica gel, usingpetroleum ether/dichloromethane/ethyl acetate (5:0:5 to 0:5:5) aseluent. The title product was obtained as a yellow oil (301 mg, 67%).

LCMS (ESI-APCI) m/z 334.2 (M+H)⁺

Step 3: 3-((Azetidin-3-yloxy)methyl)-1-methyl-1H-pyrazole hydrochloride

1-Chloroethyl chloroformate (70.8 μL, 0.65 mmol) was added to a solutionof 3-((1-benzhydrylazetidin-3-yloxy)-methyl-1H-pyrazole (218 mg, 0.65mmol) in dichloromethane (7 mL) at 0° C. The reaction mixture wasstirred for 2 hours. Ethanol (9 mL) was added and the reaction mixturewas stirred for an additional 1 hour at room temperature. Afterconcentration to dryness, the crude mixture was triturated in pentane(4×10 mL) to give a yellow oil (133 mg, quantitative) which was used inthe next step without further purification.

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 9.97 and 9.66 (s, NH₂), 7.34 (s, 1H),6.27 (s, 1H), 4.52 (s, 2H), 4.14-4.10 (m, 2H), 3.97-3.91 (m, 5H),3.78-1.76 (m, 1H).

Step 4:(E)-6-(3-(3-((1-Methyl-1H-pyrazol-3-yl)methoxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one

3-((Azetidin-3-yloxy)methyl)-1-methyl-1H-pyrazole hydrochloride (120 mg,0.59 mmol), EDCI (113 mg, 0.59 mmol), HOBt (80.0 mg, 0.59 mmol) anddiisopropylethylamine (3.0 mL, 2.01 mmol) were successively added to asolution of(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acidhydrochloride (100 mg, 0.42 mmol) in dimethylformamide (10 mL) at roomtemperature. The reaction mixture was stirred overnight and then dilutedby addition of ethyl acetate (30 mL) and water (20 mL). The aqueouslayer was separated and extracted with ethyl acetate (2×30 mL). Thecombined organic phases were washed with a saturated solution of sodiumchloride (4×100 mL), dried over sodium sulfate, filtered andconcentrated to dryness. The residue was purified by chromatography onsilica gel using dichloromethane/methanol (98:2 to 95:5) as eluent. Thetrituration of the residue in methanol allowed the isolation of thetitle product as a white solid (39 mg, 27%).

LCMS (ESI-APCI) m/z 368.2 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 10.68 (s, NH), 8.33 (s, 1H), 8.01(s, 1H), 7.64 (d, J=2.2 Hz, 1H), 7.38 (d, J=15.6 Hz, 1H), 6.70 (d,J=15.6 Hz, 1H), 6.24 (d, J 2.2 Hz, 1H), 4.45-438 (m, 2H), 4.38 (s, 2H),4.11-4.04 (m, 2H), 3.8 (s, 3H), 3.7-3.6 (m, 1H), 2.90 (t, J=7.6 Hz, 2H),2.51 (t, J=7.6 Hz, 2H). The CH₂ at 2.5 ppm is partially hidden by DMSO.

Example 39(E)-6-(3-Oxo-3-(3-(thiazol-5-ylmethoxy)azetidin-1-yl)prop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E39) Step 1: 5-(Chloromethyl)thiazole hydrochloride

Thionyl chloride (608 mL, 8.34 mmol) was added to a solution ofthiazol-5-methanol (800 mg, 6.95 mmol) in THF (4.3 mL) at 0° C. Thereaction mixture was stirred at room temperature for 30 minutes and thenat 50° C. for 2 hours. After cooling down to room temperature, themixture was concentrated to dryness. The title compound was used in thenext step without further purification.

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 9.14 (s, 1H), 7.97 (s, 1H), 5.12 (s,2H).

Step 2: tert-Butyl 3-(thiazol-5-ylmethoxy)-azetidine-1-carboxylate

Sodium hydride (60% in oil, 292 mg, 7.30 mmol) was added to a solutionof tert-butyl 3-hydroxyazetidine-1-carboxylate (602 mg, 3.47 mmol) indimethylformamide (8 mL) at room temperature. The reaction mixture wasstirred for 30 minutes prior to the addition of a solution of5-(chloromethyl)thiazole hydrochloride (1.18 g, 6.85 mmol) anddiisopropylethylamine (2.42 mL, 13.89 mmol) in dimethylformamide (3 mL)at 0° C. The reaction mixture was then heated up to 80° C. and stirredovernight. Since the LCMS monitoring still indicated the presence ofstarting material, an additional portion of sodium hydride (60% in oil,139 mg, 3.47 mmol) was added. The reaction mixture was then stirredagain at 80° C. After 17 hours stirring at 80° C., the reaction mixturewas partitioned between ethyl acetate (20 mL) and water (20 mL). Theaqueous phase was separated and extracted with ethyl acetate (2×40 mL).The combined organic phases were washed with a solution of sodiumhydroxide (5×50 mL) and with brine (3×100 mL), dried over sodiumsulfate, filtered and concentrated to dryness. The residue was purifiedby chromatography on silica gel, using petroleumether/dichloromethane/ethyl acetate (7/0/3 to 2/0/8, then 0:5:5 to0/2/8) as eluent. A second purification was performed on silica gel,using petroleum dichloromethane/acetone (9/1 to 8/2) as eluent. Thetitle product was obtained as a yellow oil (150 mg, 16%).

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 8.74 (s, 1H), 7.72 (s, 1H), 4.62 (s,2H), 4.26-4.23 (m, 1H), 4.01-3.97 (m, 2H), 3.79-3.75 (m, 2H), 1.50 (s,9H).

Step 3: 5-((Azetidin-3-yloxy)methyl)thiazole hydrochloride

A solution of HCl in diethylether (2N, 5.5 mL) was added to a solutionof tert-butyl 3-(thiazol-5-ylmethoxy)-azetidine-1-carboxylate (150 mg,0.55 mmol) in diethylether (2 mL) at room temperature. The reactionmixture was stirred 30 minutes then concentrated to dryness. Aftertrituration in diethyl ether (10 mL), the title compound was obtained asa yellow solid (113 mg, quantitative).

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 9.16 (s, 1H), 7.92 (s, 1H), 4.76 (s,2H), 4.48-4.44 (m, 1H), 4.15-4.05 (m, 2H), 3.82-3.77 (m, 2H).

Step 4:(E)-6-(3-Oxo-3-(3-(thiazol-5-ylmethoxy)azetidin-1-yl)prop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one

5-((Azetidin-3-yloxy)methyl)thiazole hydrochloride (113 mg, 0.54 mmol),EDCI (121 mg, 0.63 mmol), HOBt (87.7 mg, 0.63 mmol) anddiisopropylethylamine (183 μL, 1.05 mmol) were successively added to asolution of(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acidhydrochloride (107 mg, 0.42 mmol) in dimethylformamide (10 mL) at roomtemperature. The reaction mixture was stirred overnight then partitionedbetween ethyl acetate (30 mL) and water (20 mL). The aqueous layer wasseparated and extracted with ethyl acetate (2×20 mL). The combinedorganic phases were washed with a saturated solution of sodium chloride(3×30 mL), dried over sodium sulfate, filtered and concentrated todryness. The residue was purified by chromatography on silica gel usingdichloromethane/methanol (10:0 to 98:2) as eluent then on C₁₈ usingdichloromethane/methanol (98:2) as eluent. In order to reach therequired purity, the residue was finally recrystallized in methanol toafford the title product as a white solid (2.8 mg, 2%).

LCMS (ESI-APCI) m/z 371.1 (M+H)⁺

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 8.89 (br s, NH), 8.84 (s, 1H), 8.33(s, 1H), 7.82 (s, 1H), 7.63 (s, 1H), 7.58 (d, J=15.6 Hz, 1H), 6.39 (d,J=15.6 Hz, 1H), 4.77-4.74 (m, 2H), 4.75-4.41 (m, 2H), 4.31-4.27 (m, 1H),4.17-4.15 (m, 1H), 4.05-4.01 (m, 1H), 2.99 (t, J=7.6 Hz, 2H), 2.7 (t,J=7.6 Hz, 2H).

Example 40(E)-6-(3-(3-(Furan-2-ylmethoxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E40) Step 1: 2-(Chloromethyl)furan

Triethylamine (10.3 mL, 74 mmol) and a solution of thionyl chloride (2.9mL, 40.7 mmol) in chloroforme (19 mL) were successively added to asolution of furfuryl alcohol (3.7 g, 37 mmol) in chloroforme (38 mL) at0° C. The reaction mixture was then allowed to reach room temperatureand stirred for 2 hours. Water (50 mL) was then added and the organicphase was separated and washed with water (2×50 mL), dried over sodiumsulphate, filtered and concentrated to dryness. The resulting residuewas distilled under reduced pressure (T=50° C., P=10 mbars) to give acolorless oil (2.0 g, 45%) which was directly used in the next step.

¹H NMR (CDCl₃, 400 MHz): 7.43 (s, 1H), 6.39-6.35 (m, 2H), 4.60 (s, 2H).

Step 2: 1-Benzhydryl-3-(furan-2-ylmethoxy)-azetidine

Sodium hydride (60% in oil, 877 mg, 22 mmol) was added to a solution of1-benzhydryl-3-azetidin-3-ol (2.62 g, 11 mmol) in dimethylformamide (15mL) at room temperature. The reaction mixture was stirred for 30 minutesprior to the addition of 2-(chloromethyl)furan (2.94 g, 25.2 mmol) insolution in dimethylformamide (10 mL). The reaction mixture was thenstirred at room temperature overnight. The reaction mixture was dilutedby addition of ethyl acetate (50 mL) and water (50 mL). The aqueouslayer was separated and extracted with ethyl acetate (2×50 mL). Thecombined organic phases were washed with a saturated solution of sodiumchloride (3×30 mL), dried over sodium sulphate, filtered andconcentrated to dryness. The residue was purified by chromatography onsilica gel, using petroleum ether/ethyl acetate (9:1) as eluent. Thetitle product was obtained as a yellow oil (3.2 g, 91%).

LCMS (ESI-APCI) m/z 320.2 (M+H)⁺

Step 3: 3-(Furan-2-ylmethoxy)-azetidine hydrochloride

1-Chloroethyl chloroformate (534 μL, 4.93 mmol) was added to a solutionof 1-benzhydryl-3-(furan-2-ylmethoxy)-azetidine (1.5 g, 4.7 mmol) indichloromethane (36 mL) at 0° C. The reaction mixture was then heated upto 40° C. and stirred for 2 hours. Ethanol (50 mL) was added and thereaction mixture was stirred for an additional 1 h30 at 40° C. Afterconcentration to dryness, the crude mixture was triturated in petroleumether (2×20 mL) to give a yellow oil (558 mg, 74%) which was used in thenext step without further purification.

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 9.22 (br s, NH₂), 7.68 (m, 1H),6.5-6.45 (m, 2H), 4.47 (s, 2H), 4.39-4.45 (m, 1H), 4.06-4.01 (m, 2H),3.48-3.42 (m, 2H).

Step 4:(E)-6-(3-(3-(Furan-2-ylmethoxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one

3-(Furan-2-ylmethoxy)-azetidine hydrochloride (558 mg, 2.94 mmol), EDCI(563 mg, 2.94 mmol), HOBt (410 mg, 2.94 mmol) and diisopropylethylamine(853 μL, 4.9 mmol) were successively added to a solution of(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acidhydrochloride (500 mg, 1.96 mmol) in dimethylformamide (50 mL) at roomtemperature. The reaction mixture was stirred for 2 days and thendiluted by addition of ethyl acetate (50 mL) and water (50 mL). Theaqueous layer was separated and successively extracted with ethylacetate (2×50 mL) and dichloromethane (2×50 mL). The combined organicphases were washed with a saturated solution of sodium chloride (3×60mL), dried over sodium sulfate, filtered and concentrated to dryness.The residue was purified by chromatography on silica gel, usingdichloromethane/methanol (10:0 to 95:5) as eluent. After trituration ofthe isolated solid in diethylether, the title product was obtained as awhite solid (236 mg, 34%).

LCMS (ESI-APCI) m/z 354.2 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 10.69 (s, NH), 8.34 (s, 1H), 8.01(s, 1H), 7.68 (s, 1H), 7.39 (d, J=15.6 Hz, 1H), 6.69 (d, J=15.6 Hz, 1H),6.49-6.45 (m, 2H), 4.45 (s, 2H), 4.44-4.39 (m, 2H), 4.1-4.02 (m, 2H),3.66-3.63 (m, 1H), 2.91 (t, J=7.6 Hz, 2H), 2.51 (t, J=7.6 Hz, 2H). TheCH₂ at 2.5 ppm is partially hidden by DMSO.

Example 41(E)-1′-Methyl-6-(3-oxo-3-(3-(thiophen-2-ylmethoxy)azetidin-1-yl)prop-1-enyl)-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one(E41) Step 1: N-Boc ethylisopinecotate

Boc₂O (15.8 g, 71.4 mmol) and triethylamine (10 mL, 77.8 mmol) weresuccessively added to a solution of ethylisopinecotate (10.2 g, 64.9mmol) in dichloromethane (50 mL) at room temperature. The reactionmixture was stirred overnight. The reaction mixture was diluted byaddition of a saturated solution of ammonium chloride (50 mL). Theaqueous layer was separated and extracted with dichloromethane (2×50mL). The combined organic phases were dried over sodium sulphate,filtered and concentrated to dryness. The title product was obtained asa yellow oil (16.7 g, 100%).

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 4.18 (q, J=6.8 Hz, 2H), 4.08-4.04 (m,2H), 2.88 (m, 2H), 2.49-2.45 (m, 1H), 1.93-1.88 (m, 2H), 1.71-1.63 (m,2H), 1.50 (s, 9H), 1.30 (t, J=6.8 Hz, 3H).

Step 2: 1-tert-Butyl 4-ethyl4-((2-amino-5-bromopyridin-3-yl)methyl)piperidine-1,4-dicarboxylate

Freshly prepared LDA (14 mL, 1M in THF, 14 mmol) was added dropwise over15 minutes to a cold (−78° C.) solution of5-bromo-3-(bromomethyl)pyridine-2-amine hydrobromide (4.8 g, 14 mmol) inTHF (56 mL) under argon. The reaction mixture was stirred for anadditional 15 minutes. In a separate flask, freshly prepared LDA (42 mL,1M in THF, 42 mmol) was added dropwise over 30 minutes to a coldsolution of N-Boc ethylisopinecotate (10.9 g, 42 mmol) was in THF (100ml). The reaction mixture was stirred for an additional 30 minutes. Thelithium salt of N-Boc ethylisopinecotate was then canulated dropwiseover 30 minutes to the lithium salt of5-bromo-3-(bromomethyl)pyridine-2-amine. The mixture was stirred at −78°C. for 2 hours and allowed to warm to room temperature. The reactionmixture was quenched with a saturated solution of ammonium chloride (150mL) and ethyl acetate (150 mL) was added. The organic phase was washedwith water (2×50 mL) and brine (100 mL), dried over sodium sulphate,filtered and concentrated to dryness. The residue was purified bychromatography on silica gel, using dichloromethane/AcOEt (95:5 to 9:1)as eluent. The title product was obtained as a yellow oil (1.25 g, 20%).

LCMS (ESI-APCI) m/z 442.1-444.1 (M+H)⁺

Step 3: tert-Butyl6-bromo-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-1′-carboxylate

Sodium hydride (201 mg, 5.3 mmol) was added to a solution of1-tert-butyl 4-ethyl4-((2-amino-5-bromopyridin-3-yl)methyl)piperidine-1,4-dicarboxylate(1.71 g, 3.87 mmol) suspended in THF (17 mL) at room temperature. Thereaction mixture was stirred for 1 hour and then diluted by addition ofwater (50 mL). The resulting precipitate was filtered and washed withpentane. The title compound was obtained as a beige solid (1.2 g, 78%).

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 8.23 (s, 1H), 8.03 (br s, 1H), 7.61(s, 1H), 3.7-3.45 (m, 4H), 2.84 (s, 2H), 2.00-1.88 (m, 2H), 1.45 (s,9H), 1.45-1.40 (m, 2H).

Step 4: (E)-tert-Butyl6-(3-ethoxy-3-oxoprop-1-enyl)-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-1′-carboxylate

Ethyl acrylate (2.3 mL, 21.2 mmol), diisopropylethylamine (3.7 mL, 21.2mmol) and P(o-tolyl)₃ (323 mg, 1.06 mmol) were successively added to asuspension of tert-butyl6-bromo-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-V-carboxylate(2.10 g, 5.3 mmol) in propionitrile (20 mL) and dimethylformamide (5 mL)in a sealed tube. The resulting mixture was then purged with argon priorto the addition of palladium acetate (120 mg, 0.53 mmol). The mixturewas purged with argon again and refluxed overnight. The reaction mixturewas then filtered on Celite®. The filtrate was concentrated to drynessand the residue was solubilized in dichloromethane (100 mL). Theresulting solution was washed with a saturated solution of ammoniumchloride (100 mL), dried over sodium sulfate, filtered and concentratedto dryness. The residue was precipitated indichloromethane/diethylether/pentane, the title product was obtained asan off-white solid (1.52 g, 70%).

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 8.39 (br s, 1H), 8.31 (s, 1H), 7.66(s, 1H), 7.61 (d, J=16 Hz, 1H), 6.40 (d, J=16 Hz, 1H), 4.27 (q, J=7.2Hz, 2H), 3.65-3.40 (m, 4H), 2.89 (s, 2H), 2.05-1.95 (m, 2H), 1.46 (s,9H), 1.46-1.43 (m, 2H), 1.34 (t, J=7.2 Hz, 3H).

Step 5: (E)-Ethyl3-(2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-6-yl)acrylate

Trifluoroacetic acid (5 mL) was added to a suspension of (E)-tert-butyl6-(3-ethoxy-3-oxoprop-1-enyl)-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-1′-carboxylate(1.52 g, 3.66 mmol) in dichloromethane (20 mL). The reaction mixture wasstirred at room temperature for 1 hour and concentrated to dryness. Theresulting residue was partitioned between an aqueous solution of sodiumhydroxide (1N, 60 mL) and dichloromethane (40 mL). The aqueous layer wasseparated and extracted with dichloromethane (2×70 mL). The combinedorganic phases were dried over sodium sulfate, filtered and concentratedto dryness. The title product was obtained as a pale yellow solid (904mg, 79%).

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 8.29 (s, 1H), 8.27 (br s, 1H), 7.68(s, 1H), 7.61 (d, J=16 Hz, 1H), 6.40 (d, J=16 Hz, 1H), 4.27 (q, J=7.2Hz, 2H), 3.06-3.04 (m, 2H), 2.94 (s, 2H), 2.90-2.87 (m, 2H), 1.99-1.96(m, 2H), 1.44-1.40 (m, 2H), 1.34 (t, J=7.6 Hz, 3H).

Step 6: (E)-Ethyl3-(1′-methyl-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-6-yl)acrylate

Sodium triacetoxyborohydride (1.2 g, 5.73 mmol) and paraformaldehyde(172 mg, 5.73 mmol) were successively added to a suspension of (E)-ethyl3-(2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-6-yl)acrylate(904 mg, 2.87 mmol) in 1,2-dichloroethane (40 mL) at room temperature.The reaction mixture was then heated up to 70° C. and stirred for 2hours. After cooling down to room temperature, the reaction mixture wasdiluted by addition of ethyl acetate (50 mL) and water (50 mL). Theaqueous layer was separated and extracted with ethyl acetate (2×50 mL).The combined organic phases were washed with a saturated solution ofsodium hydrogenocarbonate (3×60 mL), dried over sodium sulfate, filteredand concentrated to dryness. The title product was obtained as a whitesolid (862 mg, 91%).

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 8.29 (s, 1H), 8.24 (br s, 1H), 7.67(s, 1H), 7.61 (d, J=16 Hz, 1H), 6.40 (d, J=16 Hz, 1H), 4.27 (q, J=7.2Hz, 2H), 2.88 (s, 2H), 2.64-2.60 (m, 2H), 2.42-2.40 (m, 2H), 2.32 (s,2H), 2.08-2.04 (m, 2H), 1.54-1.51 (m, 2H), 1.34 (t, J=7.2 Hz, 3H).

Step 7: (E)-3-(7-Oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylicacid hydrochloride

An aqueous solution of sodium hydroxide (1N, 7.83 mL) was added to asolution of (E)-ethyl3-(1′-methyl-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-6-yl)acrylate(860 mg, 2.61 mmol) in a mixture of dichloromethane (10 mL) and ethanol(10 mL) at room temperature. The reaction mixture was stirred at 45° C.overnight then concentrated to dryness. The residue was acidified byaddition of an aqueous solution of hydrochloric acid (1N, 30 mL) untilpH 1. The resulting solid was filtered and washed with water and diethylether. The title product was obtained as a white solid (586 mg, 66%).

LCMS (ESI-APCI) m/z 302.2 (M+H)⁺

Step 8:(E)-1′-Methyl-6-(3-oxo-3-(3-(thiophen-2-ylmethoxy)azetidin-1-yl)prop-1-enyl)-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one

3-(Thiophen-2-ylmethoxy)-azetidine hydrochloride (45.8 mg, 0.22 mmol),EDCI (40.26 mg, 0.21 mmol), HOBt (28.5 mg, 0.21 mmol) anddiisopropylethylamine (62 μL, 0.35 mmol) were successively added to asolution of(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acidhydrochloride (47.0 mg, 0.14 mmol) in dimethylformamide (5 mL) at roomtemperature. The reaction mixture was stirred overnight and then dilutedby addition of ethyl acetate (20 ml) and water (20 mL). The aqueouslayer was separated and extracted with ethyl acetate (2×20 mL). Thecombined organic phases were washed with a saturated solution of sodiumchloride (3×20 mL), dried over sodium sulfate, filtered and concentratedto dryness. The residue was purified by chromatography on silica gelusing dichloromethane/methanol (95:5 to 0:1) as eluent. Afterprecipitation in a mixture dichloromethane/diethylether/pentane, thetitle product was obtained as a white solid (12 mg, 24%).

LCMS (ESI-APCI) m/z 453.1 (M+H)⁺

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 8.33 (s, 1H), 8.22 (s, 1H), 7.68 (s,1H), 7.62 (d, J=15.6 Hz, 1H), 7.41-7.38 (m, 1H), 7.10-7.04 (m, 2H), 6.44(d, J=15.6 Hz, 1H), 4.76-4.74 (m, 2H), 4.53-4.45 (m, 2H), 4.32-4.20 (m,2H), 4.09-4.04 (m, 1H), 2.93 (s, 2H), 2.72-2.67 (m, 2H), 4.50-2.38 (m,2H), 2.38 (s, 3H), 2.16-2.09 (m, 2H), 1.68-1.65 (m, 2H).

Example 42(E)-7-(3-Oxo-3-(3-(thiophen-2-ylmethoxy)azetidin-1-yl)prop-1-enyl)-4,5-dihydro-1H-pyrido[2,3-e][1,4]diazepin-2(3H)-one(E42) Step 1: (E)-Methyl 2-(4-methoxybenzylideneamino)acetate

Triethylamine (4.6 mL, 33 mmol) and glycine methyl ester hydrochloride(3.8 g, 30.26 mmol) were successively added to a solution ofp-anisaldehyde (2.0 g, 14.7 mmol) in dichloromethane (150 mL) at 0° C.Sodium sulfate (10 g) was added and the reaction mixture was stirredovernight at room temperature. The reaction mixture was then filteredand concentrated to dryness. The resulting residue was portioned inethyl acetate and filtered in order to remove the triethylamine salts.The title compound was obtained as a pale yellow solid (4.43 g, 100%).

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 8.22 (s, 1H), 7.23 (d, J=8.4 Hz, 2H),6.93 (d, J=8.4 Hz, 2H), 4.39 (s, 2H), 3.85 (s, 3H), 3.78 (s, 3H).

Step 2: Methyl 2-(4-methoxybenzylamino)acetate

Sodium borohydride (438 mg, 1.2 mmol) was added to a solution of(E)-methyl 2-(4-methoxybenzylideneamino)acetate (2.0 g, 9.6 mmol) in amixture of methanol (22 mL) and THF (11 mL) at 0° C. The reactionmixture was stirred 1 hour at room temperature then partionned between asolution of saturated ammonium chloride (20 mL) and ethyl acetate (30mL). The aqueous phase was separated and extracted with ethyl acetate(3×50 mL). The combined organic phases were dried over sodium sulfate,filtered and concentrated to dryness. The title compound was obtained asa white oil (1.7 g, 85%).

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 7.31 (m, 2H), 6.92 (m, 2H), 3.85 (s,2H), 3.83 (s, 3H), 3.78 (s, 3H), 3.48 (s, 2H), 2.49 (br s, 1H).

Step 3: Methyl2-(((2-amino-5-bromopyridin-3-yl)methyl)(4-methoxybenzyl)amino)acetate

Methyl 2-(4-methoxybenzylamino)acetate (760 mg, 3.63 mmol) andtriethylamine (840 μL, 6.60 mmol) were successively added to a solutionof 5-bromo-3-(bromomethyl)pyridine-2-amine hydrobromide (1.0 g, 3.30mmol) in DMF (17 mL) at room temperature. The reaction mixture wasstirred for 8 hours then diluted by addition of water (50 mL) and ethylacetate (50 mL). The aqueous phase was separated and extracted withethyl actetate (3×50 mL). The combined organic phases were washed with asaturated solution of sodium chloride (3×50 mL), dried over sodiumsulphate, filtered and concentrated to dryness. The title compound wasobtained as an orange oil (1.05 g, 93%) which was used in the next stepwithout further purification.

LCMS (ESI-APCI) m/z 394.1 (M+H)⁺

Step 4:7-Bromo-4-(4-methoxybenzyl)-4,5-dihydro-1H-pyrido[2,3-e][1,4]diazepin-2(3H)-one

Sodium hydride (60% in oil, 140 mg, 3.40 mmol) was added to a solutionof methyl2-(((2-amino-5-bromopyridin-3-yl)methyl)(4-methoxybenzyl)amino)acetate(1.05 g, 2.66 mmol) in DMSO (17 mL) at room temperature. The reactionmixture was stirred overnight then diluted by addition of water (45 mL).After 2 hours stirring at room temperature, the reaction mixture wasfiltered. The resulting solid was dried under high vacuum to give thetitle compound as a yellow solid (600 mg, 63%) ¹H NMR (DMSO-d₆, 400MHz): δ (ppm): 10.37 (s, 1H), 8.37 (s, 1H), 7.88 (s, ¹H), 7.19 (d, J=8.4Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 3.81 (s, 2H), 3.75 (s, 3H), 3.62 (s,2H), 3.39 (s, 2H).

Step 5: (E)-tert-Butyl3-(4(4-methoxybenzyl)-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylate

tert-Butyl acrylate (972 μL, 6.64 mmol), diisopropylethylamine (612 μL,3.47 mmol) and P(o-tolyl)₃ (100 mg, 0.33 mmol) were successively addedto a suspension of7-bromo-4-(4-methoxybenzyl)-4,5-dihydro-1H-pyrido[2,3-e][1,4]diazepin-2(3H)-one(600 mg, 1.66 mmol) in propionitrile (10 mL) and dimethylformamide (2mL). The resulting mixture was then purged with argon prior to theaddition of palladium acetate (40 mg, 0.16 mmol). The mixture was purgedwith argon a second time and refluxed overnight. The reaction mixturewas then filtered on Celite®. The filtrate was concentrated to drynessand the residue was solubilized in ethyl acetate (30 mL). The aqueousphase was separated and extracted with ethyl acetate (2×40 mL). Thecombined organic phases were washed with a saturated solution of sodiumchloride (2×20 mL), dried over sodium sulfate, filtered and concentratedto dryness. The residue was purified by chromatography on silica gel,using dichloromethane/ethyl actetate (7:3) as eluent. The title productwas obtained as a yellow solid (112 mg, 16%).

LCMS (ESI-APCI) m/z 410.2 (M+H)⁺

Step 6:(E)-3-(4-(4-Methoxybenzyl)-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylicacid hydrochloride

Trifluoroacetic acid (1 mL) was added to a suspension of (E)-tert-butyl3-(4(4-methoxybenzyl)-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylate(112 mg, 0.27 mmol) in dichloromethane (1 mL) at room temperature. Thereaction mixture was then stirred for 1 hour and concentrated todryness. The resulting residue was suspended in a solution ofhydrochloric acid in dioxane 4N (2 mL). After 10 minutes stirring atroom temperature, the precipitate was filtered and washed with diethylether to afford the title product as a pale yellow solid (110 mg,quantitative).

LCMS (ESI-APCI) m/z 354.2 (M+H)⁺

Step 7:(E)-4-(4-Methoxybenzyl)-7-(3-oxo-3-(3-(thiophen-2-ylmethoxy)azetidin-1-yl)prop-1-enyl)-4,5-dihydro-1H-pyrido[2,3-e][1,4]diazepin-2(3H)-one

3-(Thiophen-2-ylmethoxy)-azetidine hydrochloride (231 mg, 1.12 mmol),EDCI (215 mg, 1.12 mmol), HOBt (152 mg, 1.12 mmol) anddiisopropylethylamine (321 μL, 1.87 mmol) were successively added to asolution of(E)-3-(4-(4-methoxybenzyl)-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylicacid hydrochloride (292 mg, 0.75 mmol) in dimethylformamide (20 mL) atroom temperature. The reaction mixture was stirred overnight and thendiluted by addition of ethyl acetate (30 ml) and water (30 mL). Theaqueous layer was separated and extracted with ethyl acetate (2×30 mL)and dichloromethane (2×20 mL). The combined organic phases were washedwith a saturated solution of sodium chloride (3×20 mL), dried oversodium sulfate, filtered and concentrated to dryness. The residue wasprecipitated from a mixture ethyl acetate/diethyl ether to afford thetitle product as an off-white solid (151 mg, 40%).

LCMS (ESI-APCI) m/z 505.2 (M+H)⁺

Step 8: (E)-2-Chloropropyl2-oxo-7-(3-oxo-3-(3-(thiophen-2-ylmethoxy)azetidin-1-yl)prop-1-enyl)-2,3-dihydro-1H-pyrido[2,3-e][1,4]diazepine-4(5H)-carboxylate

1-Chloroethyl chloroformate (49 μL, 0.45 mmol) was added to a solutionof(E)-4-(4-methoxybenzyl)-7-(3-oxo-3-(3-(thiophen-2-ylmethoxy)azetidin-1-yl)prop-1-enyl)-4,5-dihydro-1H-pyrido[2,3-e][1,4]diazepin-2(3H)-one(151 mg, 0.3 mmol) in dichloroethane (4.5 mL) at 0° C. The reactionmixture was stirred for 1 hour at room temperature and for 2 hours atreflux. After concentration to dryness, the residue was purified bychromatography on silica gel, using dichloromethane/methanol (98:2) aseluent. A final trituration in diethyl ether afforded the title productas a white solid (75 mg, 51%).

LCMS (ESI-APCI) m/z 491.1 (M+H)⁺

Step 9:(E)-7-(3-Oxo-3-(3-(thiophen-2-ylmethoxy)azetidin-1-yl)prop-1-enyl)-4,5-dihydro-1H-pyrido[2,3-e][1,4]diazepin-2(3H)-one

A solution of (E)-2-chloropropyl2-oxo-7-(3-oxo-3-(3-(thiophen-2-ylmethoxy)azetidin-1-yl)prop-1-enyl)-2,3-dihydro-1H-pyrido[2,3-e][1,4]diazepine-4(5H)-carboxylate(75 mg, 0.15 mmol) in methanol (3 mL) was refluxed for 2 hours. Afterconcentration to dryness, the residue was triturated in methanol. Thetitle product was obtained as a white solid (75 mg, 19%).

LCMS (ESI-APCI) m/z 385.1 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 11.10 (s, 1H), 9.77 (s, 1H), 8.72(s, 1H), 8.23 (s, 1H), 7.57-7.55 (m, 1H), 7.48 (d, J=15.6 Hz, 1H), 7.12(s, 1H), 7.05-7.02 (m, 1H), 6.80 (d, J=15.6 Hz, 1H), 4.68 (s, 2H),4.49-4.46 (m, 2H), 4.26 (s, 2H), 4.15-4.09 (m, 2H), 3.84 (s, 2H),3.77-3.74 (m, 1H).

Example 43 (E)-Ethyl2-(2-oxo-6-(3-oxo-3-(3-(thiophen-2-ylmethoxy)azetidin-1-yl)prop-1-enyl)-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)acetate(E43) Step 1: Ethyl 2-((2-amino-5-bromopyridin-3-yl)methylamino)acetate

Glycine ethyl ester hydrochloride (805 mg, 5.7 mmol) and triethylamine(2.6 mL, 18.46 mmol) were successively added to a solution of5-bromo-3-(bromomethyl)pyridin-2-amine hydrobromide (2, 5.7 mmol) indimethylformamide (65 mL) at room temperature. The reaction mixture wasstirred overnight then partitioned between ethyl acetate (70 ml) andwater (100 mL). The aqueous phase was separated and extracted with ethylacetate (2×50 mL). The combined organic phases were washed with asaturated solution of sodium chloride (3×40 mL), dried over sodiumsulfate, filtered and concentrated to dryness. The residue was purifiedby chromatography on silica gel, using dichloromethane/methanol (10:0 to95:5) as eluent. The title product was obtained as a yellow solid (1.1g, 68%).

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 7.96 (s, 1H), 7.29 (s, 1H), 5.66 (brs, NH2), 4.15 (q, J=7.6 Hz, 2H), 3.64 (s, 2H), 3.31 (s, 2H), 1.21 (t,J=7.6 Hz, 3H).

Step 2: Ethyl2-(6-bromo-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)acetate

CDI (1.8 g, 114 mmol) was added to a solution of ethyl2-((2-amino-5-bromopyridin-3-yl)methylamino)acetate (1.1 g, 38.17 mmol)in dioxane (36 mL). The reaction mixture was stirred at reflux for 5hours and then concentrated to dryness. The residue was partitionedbetween dichloromethane (40 mL) and water (30 mL). The aqueous phase wasseparated and extracted with dichloromethane (2×30 mL). The combinedorganic phases were washed with brine (50 mL), dried over sodiumsulfate, filtered and concentrated to dryness. The isolated compound wasfinally precipitated from a mixture dichloromethane/pentane to give thetitle product as a yellow solid (670 mg, 56%).

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 8.16 (s, 1H), 7.87 (s, 1H), 7.41 (s,1H), 4.48 (s, 2H), 4.14 (q, J=7.6 Hz, 2H), 4.11 (s, 2H), 1.23 (t, J=7.6Hz, 3H).

Step 3: (E)-tert-Butyl3-(3-(2-ethoxy-2-oxoethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl)acrylate

tert-Butyl acrylate (1.25 mL, 8.53 mmol), diisopropylethylamine (730 μL,4.26 mmol) and P(o-tolyl)₃ (130 mg, 0.43 mmol) were successively addedto a suspension of ethyl2-(6-bromo-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)acetate (670mg, 2.13 mmol) in propionitrile (11 mL) and dimethylformamide (2.5 mL).The resulting mixture was purged with argon prior to the addition ofpalladium acetate (48 mg, 0.213 mmol). The mixture was purged with argona second time and refluxed overnight. The reaction mixture was thenfiltered on Celite® and washed with ethyl acetate (75 mL) anddichloromethane (75 mL). The filtrate was concentrated to dryness andthe residue was partitioned between dichloromethane (50 mL) and water(50 mL). The aqueous phase was separated and extracted withdichloromethane (2×100 mL). The combined organic phases were washed witha saturated solution of sodium chloride (3×100 mL), dried over sodiumsulfate, filtered and concentrated to dryness. The residue wasprecipitated from a mixture dichloromethane/diethylether to afford thetitle product as a white solid (460 mg, 60%).

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 8.27 (s, 1H), 7.58 (s, 1H), 7.52 (s,1H), 7.48 (d, J=16 Hz, 1H), 6.28 (d, J=16 Hz, 1H), 4.58 (s, 2H), 4.25(q, J=6.8 Hz, 2H), 4.19 (s, 2H), 1.52 (s, 9H), 1.30 (t, J=6.8 Hz, 3H).

Step 4:(E)-3-(3-(2-Ethoxy-2-oxoethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl)acrylicacid hydrochloride

Trifluoroacetic acid (5 mL) was added to a solution of (E)-tert-butyl3-(3-(2-ethoxy-2-oxoethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl)acrylate(460 mg, 1.27 mmol) in dichloromethane (5 mL) at room temperature. Thereaction mixture was stirred at room temperature for 30 minutes. Afterconcentration to dryness, the residue was suspended in a solution ofhydrochloric acid in dioxane 4N (10 mL). The resulting white precipitatewas filtered and washed with diethyl ether to give the title compound(470 mg; quantitative).

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 8.37 (s, 1H), 7.95 (s, 1H), 7.54 (d,J=15.6 Hz, 1H), 6.48 (d, J=15.6 Hz, 1H), 4.52 (s, 2H), 4.14 (m, 4H),1.22 (t, J=6.8 Hz, 3H)

Step 5: (E)-Ethyl2-(2-oxo-6-(3-oxo-3-(3-(thiophen-2-ylmethoxy)azetidin-1-yl)prop-1-enyl)-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)acetate

3-(Thiophen-2-ylmethoxy)-azetidine hydrochloride (243 mg, 1.18 mmol),EDCI (227 mg, 1.18 mmol), HOBt (160 mg, 0.6 mmol) anddiisopropylethylamine (340 μL, 1.97 mmol) were successively added to asolution of(E)-3-(3-(2-ethoxy-2-oxoethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl)acrylicacid hydrochloride (270 mg, 0.79 mmol) in dimethylformamide (15 mL) atroom temperature. The reaction mixture was stirred for 2 days thenpartitioned between ethyl acetate (30 mL) and water (40 mL). The aqueouslayer was separated and successively extracted with ethyl acetate (2×30mL) and dichloromethane (2×30 mL). The combined organic phases werewashed with a saturated solution of sodium chloride (3×40 mL), driedover sodium sulfate, filtered and concentrated to dryness. The residuewas purified by chromatography on silica gel usingdichloromethane/methanol (10:0 to 98:2) as eluent. The title product wasobtained as an off-white solid (215 mg, 60%).

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 8.36 (s, 1H), 7.76 (s, 1H), 7.59 (d,J=15.6 Hz, 1H), 7.54 (s, 1H), 7.39 (m, 1H), 7.09-7.04 (m, 2H), 6.69 (d,J=15.6 Hz, 1H), 4.77-4.72 (m, 2H), 4.64 (s, 2H), 4.53-4.43 (m, 2H),4.31-4.17 (m, 6H), 4.08-4.03 (m, 1H), 1.35 (t, J=6.8 Hz, 3H).

Step 6: Sodium(E)-2-(2-oxo-6-(3-oxo-3-(3-(thiophen-2-ylmethoxy)azetidin-1-yl)prop-1-enyl)-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)acetate

A solution of sodium hydroxyde (1N, 438 μL, 0.44 mmol) was added to asuspension of (E)-ethyl2-(2-oxo-6-(3-oxo-3-(3-(thiophen-2-ylmethoxy)azetidin-1-yl)prop-1-enyl)-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)acetate(100 mg, 0.22 mmol) in methanol (5 mL) at room temperature. The reactionmixture was refluxed for 15 minutes then poured into cold water. Theresulting precipitate was filtered and washed with diethyl ether. Thetitle product was obtained as a white solid (53.5 mg, 54%).

LCMS (ESI-APCI) m/z 429.1 (M+H)⁺ (acid form) ¹H NMR (DMSO-d₆, 400 MHz):δ (ppm): 9.66 (br s, NH), 8.27 (s, 1H), 7.89 (s, 1H), 7.57-7.54 (m, 1H),7.36 (d, J=15.6 Hz, 1H), 7.13-7.11 (m, 1H), 7.05-7.02 (m, 1H), 6.63 (d,J=15.6 Hz, 1H), 4.67 (s, 2H), 4.48 (s, 2H), 4.48-4.43 (m, 2H), 4.18-4.05(m, 2H), 3.74-3.70 (m, 1H), 3.53 (s, 2H).

Example 44(E)-3-(2-(4-Methylpiperazin-1-yl)ethyl)-6-(3-oxo-3-(3-(thiophen-2-ylmethoxy)azetidin-1-yl)prop-1-enyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one(E44) Step 1: 2-Amino-5-bromonicotinaldehyde hydrobromide

A solution of bromine (1.05 mL, 20.0 mmol) in acetic acid (20 mL) wasadded to a solution of 2-amino-3-pyridinecarboxaldehyde (2.5 g, 20 mmol)in acetic acid (50 mL) at room temperature. The reaction mixture wasthen stirred overnight. The resulting precipitate was filtered andwashed with diethyl ether to give the title compound as a white solid(4.66 g, 80%).

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 9.82 (s, 1H), 8.32 (s, 1H), 8.26 (s,1H), 7.74 (br s, NH₂).

Step 2:5-Bromo-3-((2-(4-methylpiperazin-1-yl)ethylamino)methyl)pyridin-2-amine

Triethylamine (1.0 mL, 7.09 mmol) was added to a solution of2-amino-5-bromonicotinaldehyde hydrobromide (1.0 g, 3.54 mmol) inmethanol (24 mL) at room temperature. The reaction mixture was stirredfor 10 minutes prior to the addition of2-(4-methylpiperazin-1-yl)ethanamine (558 mg, 3.90 mmol). The reactionmixture was then stirred overnight and cooled to 0° C. Sodiumborohydride (201 mg, 5.32 mmol) was added portionwise at 0° C. and thereaction mixture was allowed to reach room temperature and stirred for 4hours. After concentration to dryness, the residue was purified bychromatography on silica gel using dichloromethane/methanol/ammoniac(10:0:0.1 to 9:1:0.1) as eluent. The title product was obtained as ayellow solid (560 mg, 48%).

LCMS (ESI-APCI) m/z 328.1-330.1 (M+H)⁺

Step 3:6-Bromo-3-(2-(4-methylpiperazin-1-yl)ethyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one

CDI (815 mg, 5.0 mmol) was added to a solution of5-bromo-3-((2-(4-methylpiperazin-1-yl)ethylamino)methyl)pyridin-2-amine(550 mg, 1.67 mmol) in dioxane (13 mL). The reaction mixture was stirredovernight at reflux. After concentration to dryness, the residue waspurified by chromatography on silica gel usingdichloromethane/methanol/ammoniac (10:0:0.1 to 9:1:0.1) as eluent. Thetitle product was obtained as a yellow solid (430 mg, 72%).

LCMS (ESI-APCI) m/z 354.1-356.1 (M+H)⁺

Step 4: (E)-tert-Butyl3-(3-(2-(4-methylpiperazin-1-yl)ethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl)acrylate

tert-Butyl acrylate (830 μL, 5.64 mmol), diisopropylethylamine (500 L,2.82 mmol) and P(o-tolyl)₃ (86 mg, 0.28 mmol) were successively added toa suspension of6-bromo-3-(2-(4-methylpiperazin-1-yl)ethyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one(500 mg, 1.41 mmol) in propionitrile (6 mL) and dimethylformamide (2mL). The resulting mixture was purged with argon prior to the additionof palladium acetate (32 mg, 0.14 mmol). The mixture was then purged asecond time with argon and refluxed overnight. The reaction mixture wasfiltered on Celite® and washed with ethyl acetate (100 mL) anddichloromethane (100 mL). The filtrate was concentrated to dryness andthe residue was solubilized in dichloromethane (100 mL). The resultingsolution was washed with a saturated solution of sodium chloride (3×100mL), dried over sodium sulfate, filtered and concentrated to dryness.The residue was purified by chromatography on silica gel usingdichloromethane/methanol/ammoniac (1:0:0.1 to 98:2:0.1) as eluent. Thetitle product was obtained as a brown solid (83 mg, 15%).

LCMS (ESI-APCI) m/z 402.3 (M+H)⁺

Step 5:(E)-3-(3-(2-(4-Methylpiperazin-1-yl)ethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl)acrylicacid hydrochloride

Trifluoroacetic acid (2 mL) was added to a suspension (E)-tert-butyl3-(3-(2-(4-methylpiperazin-1-yl)ethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl)acrylate(1.1 g, 3.76 mmol) in dichloromethane (2 mL). The reaction mixture wasstirred at room temperature for 1 hour and concentrated to dryness. Theresulting residue was solubilized in a solution of hydrochloric acid indioxane (4N, 10 mL). After 10 minutes stirring at room temperature, theprecipitate was filtered and washed with diethyl ether to afford thetitle product as a pale yellow solid (90 mg, quantitative).

LCMS (ESI-APCI) m/z 346.2 (M+H)⁺

Step 6:(E)-3-(2-(4-Methylpiperazin-1-yl)ethyl)-6-(3-oxo-3-(3-(thiophen-2-ylmethoxy)azetidin-1-yl)prop-1-enyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one

3-(Thiophen-2-ylmethoxy)-azetidine hydrochloride (38 mg, 0.18 mmol),EDCI (35 mg, 0.18 mmol), HOBt (26 mg, 0.18 mmol) anddiisopropylethylamine (54 μL, 0.31 mmol) were successively added to asolution of(E)-3-(3-(2-(4-methylpiperazin-1-yl)ethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl)acrylicacid hydrochloride (54 mg, 0.12 mmol) in dimethylformamide (6 mL) atroom temperature. The reaction mixture was stirred for 2 days and thendiluted by addition of ethyl acetate (50 mL) and water (50 mL). Theaqueous layer was separated and extracted with ethyl acetate (2×50 mL).The combined organic phases were washed with a saturated solution ofsodium chloride (3×50 mL), dried over sodium sulfate, filtered andconcentrated to dryness. The residue was purified by chromatography onsilica gel using dichloromethane/methano/ammoniac (1:0:0.1 to 9:1:0.1)as eluent. After several triturations of the compound in diethyletherand pentane and a recrystallisation from acetone, the title product wasobtained as an off-white solid (2 mg, 3%).

LCMS (ESI-APCI) m/z 497.3 (M+H)⁺

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 8.28 (s, 1H), 7.54 (d, J=15.6 Hz, 1H),7.49-4.47 (m, 2H), 7.35-7.33 (m, 1H), 7.04-6.98 (m, 2H), 6.34 (d, J=15.6Hz, 1H), 4.69 (d, J=6 Hz, 2H), 4.56 (s, 2H), 4.48-4.38 (m, 2H),4.28-4.23 (m, 1H), 4.16-4.13 (m, 1H), 4.03-3.99 (m, 1H), 3.58 (t, J=7.6Hz, 2H), 2.63 (t, J=7.6 Hz, 2H), 2.68-2.46 (m, 8H), 1.65 (s, 3H).

Example 45(E)-3-(3-((Dimethylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(3-(thiophen-2-ylmethoxy)azetidin-1-yl)prop-2-en-1-one(E45) Step 1: (E)-tert-Butyl 3-(1H-pyrrolo[2,3-b]pyridin-5-yl)acrylate

tert-Butyl acrylate (5.9 mL, 40.6 mmol), diisopropylethylamine (3.5 mL,20.3 mmol) and P(o-tolyl)₃ (618 mg, 2.0 mmol) were successively added toa suspension of 5-bromo-1H-pyrrolo[2,3-b]pyridine (2.0 g, 10.15 mmol) inpropionitrile (40 mL) and dimethylformamide (10 mL). The resultingmixture was purged with argon prior to the addition of palladium acetate(227 mg, 1.0 mmol). The mixture was then purged with argon a second timeand refluxed overnight. The reaction mixture was filtered on Celite®.The filtrate was concentrated to dryness and the residue was solubilizedin ethyl acetate (3×100 mL). The organic layers were washed with asaturated solution of sodium chloride (3×50 mL), dried over sodiumsulfate, filtered and concentrated to dryness. The crude was purified byflash chromatography on silica gel using dichloromethane/ethyl acetate(1:0 to 7:3) as eluent. The title compound was obtained as a yellowsolid (465 mg, 28%) ¹H NMR (CDCl₃, 400 MHz): δ (ppm): 10.39 (s, 1H, NH),8.49 (s, 1H), 8.12 (s, 1H), 7.75 (d, J=16 Hz, 1H), 7.38 (d, J=1.6 Hz,1H), 6.54 (d, J=2.8 Hz, 1H), 6.45 (d, J=16 Hz, 1H), 1.55 (s, 9H).

Step 2: (E)-tert-Butyl3-(3-((dimethylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acrylate

Formaldehyde (37% in water, 219 μL, 2.92 mmol) and dimethylaminehydrochloride (237 mg, 2.92 mmol) were added to a solution of(E)-tert-butyl 3-(1H-pyrrolo[2,3-b]pyridin-5-yl)acrylate (420 mg, 1.72mmol) in isopropanol (42 mL) at room temperature. The reaction mixturewas stirred at reflux overnight. Since the LCMS monitoring stillindicated the presence of remaining starting material, formaldehyde (25μL) and dimethyl amine hydrochloride (28 mg) were added. The reactionmixture was stirred at reflux for an additional 4 hours and concentratedto dryness. The residue was solubilized in an aqueous solution ofpotassium carbonate (3N, 100 mL) and the solution was extracted withethyl acetate (3×100 mL). The combined organic layers were washed with asaturated solution of sodium chloride (50 mL), dried over sodiumsulfate, filtered and concentrated to dryness. The crude was trituratedin pentane to give the title compound as a white solid (242 mg, 46%).

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 8.75 (s, 1H), 8.38 (s, 1H), 8.14 (s,1H), 7.65 (d, J=16 Hz, 1H), 6.37 (d, J=16 Hz, 1H), 3.54 (s, 2H), 2.21(s, 6H), 1.06 (s, 9H).

Step 3:(E)-3-(3-((Dimethylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acrylicacid hydrochloride

Trifluoroacetic acid (2 mL) was added to a suspension of (E)-tert-butyl3-(3-((dimethylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acrylate (120mg, 0.39 mmol) in dichloromethane (2 mL). The reaction mixture wasstirred at room temperature for 30 minutes and concentrated to dryness.The resulting residue was solubilized in a solution of hydrochloric acidin dioxane (4N, 2 mL). After 10 minutes stirring at room temperature,the precipitate was filtered and washed with diethyl ether to afford thetitle product as a pale yellow solid (112 mg, quantitative).

Step 4:(E)-3-(3-((Dimethylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(3-(thiophen-2-ylmethoxy)azetidin-1-yl)prop-2-en-1-one

3-(Thiophen-2-ylmethoxy)-azetidine hydrochloride (61 mg, 0.30 mmol),EDCI (71.5 mg, 0.37 mmol), HOBt (52 mg, 0.37 mmol) anddiisopropylethylamine (110 μL, 0.62 mmol) were successively added to asolution of(E)-3-(3-((dimethylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acrylicacid hydrochloride (70 mg, 0.25 mmol) in dimethylformamide (10 mL) atroom temperature. The reaction mixture was stirred overnight thenpartitioned between ethyl acetate (30 mL) and water (30 mL). The aqueouslayer was separated, basified with an aqueous solution of sodiumhydroxyde (2N) until pH 12 and finally extracted with ethyl acetate(2×50 mL). The combined organic phases were washed with a saturatedsolution of sodium chloride (3×50 mL), dried over sodium sulfate andconcentrated to dryness. The residue was purified by chromatography onsilica gel using dichloromethane/methanol/ammoniac (1:0:0.1 to 9:1:0.1)as eluent. The title product was obtained as a yellow solid (10 mg,10%).

LCMS (ESI-APCI) m/z 397.2 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 11.69 (s, NH), 8.51 (s, 1H), 8.29(s, ¹H), 7.56 (d, J=15.6 Hz, 1H), 7.54 (s, 1H), 7.39 (s, 1H), 7.13-7.11(m, 1H), 7.03-7.01 (m, 1H), 6.74 (d, J=15.6 Hz, 1H), 4.67 (s, 2H),4.53-4.43 (m, 2H), 4.17-4.10 (m, 2H), 3.75-3.56 (m, 1H), 3.56 (s, 2H),2.16 (s, 6H).

Example 46(E)-6-(3-Oxo-3-(3-(thiophen-2-ylmethoxy)azetidin-1-yl)prop-1-enyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one(E46) Step 1: 6-Bromo-1H-imidazo[4,5-b]pyridin-2(3H)-one

DSC (4.4 g, 17.54 mmol) was added to a suspension of5-bromopyridine-2,3-diamine (3.0 g, 15.95 mmol) in chloroform (150 mL)at room temperature. The reaction mixture was then heated up to 70° C.and stirred overnight. After concentration to dryness, the resultingbrown solid was triturated in a mixture petroleum ether/ethyl acetate(6:4, 300 mL) and washed successively with water (100 mL) and diethylether (100 mL). The title product was isolated as a brown solid (2.7 g,81%).

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 11.53 (s, 1H, NH), 11.04 (s, 1H,NH), 7.95 (d, J=2 Hz, 1H), 7.41 (d, J=2 Hz, 1H).

Step 2: (E)-tert-Butyl3-(3-(2-(4-methylpiperazin-1-yl)ethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl)acrylate

tert-Butyl acrylate (2.74 mL, 18.6 mmol), diisopropylethylamine (1.6 mL,9.8 mmol) and P(o-tolyl)₃ (272 mg, 0.89 mmol) were successively added toa suspension of 6-bromo-1H-imidazo[4,5-b]pyridin-2(3H)-one (1.0 g, 4.67mmol) in propionitrile (27 mL) and dimethylformamide (7 mL) at roomtemperature. The resulting mixture was purged with argon prior to theaddition of palladium acetate (100 mg, 0.44 mmol). The mixture was thenpurged with argon a second time and refluxed overnight. The reactionmixture was filtered on Celite® and the filtrate was concentrated todryness. The residue was partitioned between ethyl acetate (20 mL) andwater (30 mL). The organic phase was washed with a saturated solution ofsodium chloride (2×30 mL), dried over sodium sulfate, filtered andconcentrated to dryness. The residue was triturated in diethyl ether togive the title product as a brown solid (667 mg, 56%).

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 11.55 (s, 1H, NH), 11.05 (s, 1H,NH), 8.14 (s, 1H), 7.59 (s, 1H), 7.56 (d, J=16 Hz, 1H), 6.51 (d, J=14Hz, 1H), 1.49 (s, 9H).

Step 3: (E)-3-(2-Oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)acrylicacid hydrochloride

Trifluoroacetic acid (2 mL) was added to a suspension of (E)-tert-butyl3-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)acrylate (400 mg,1.54 mmol) in dichloromethane (2 mL) at room temperature. The reactionmixture was stirred for 1 hour then concentrated to dryness. Theresulting residue was suspended in a solution of hydrochloric acid indioxane 4N (2 mL). After 10 minutes stirring at room temperature, theprecipitate was filtered and washed with diethyl ether to afford thetitle product as a pale yellow solid (381 mg, quantitative).

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 11.58 (br s, NH), 11.06 (s, NH),8.14 (s, 1H), 7.60 (d, J=16 Hz, 1H), 7.58 (s, 1H), 6.51 (d, J=16 Hz,1H).

Step 4:(E)-6-(3-Oxo-3-(3-(thiophen-2-ylmethoxy)azetidin-1-yl)prop-1-enyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one

3-(Thiophen-2-ylmethoxy)-azetidine hydrochloride (127 mg, 0.62 mmol),EDCI (120 mg, 0.62 mmol), HOBt (86 mg, 0.62 mmol) anddiisopropylethylamine (180 μL, 1.03 mmol) were successively added to asolution of(E)-3-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)acrylic acidhydrochloride (100 mg, 0.41 mmol) in dimethylformamide (10 mL) at roomtemperature. The reaction mixture was stirred overnight then partitionedbetween ethyl acetate (20 mL) and water (30 mL). The aqueous layer wasseparated and successively extracted with ethyl acetate (2×20 mL) anddichloromethane (2×20 mL). The combined organic phases were washed witha saturated solution of sodium chloride (3×30 mL), dried over sodiumsulfate, filtered and concentrated to dryness. The residue was purifiedby chromatography on silica gel using dichloromethane/methanol (98:2 to93:7) as eluent. The residue was triturated in pentane to afford thetitle product as a pale orange solid (21 mg, 14%).

LCMS (ESI-APCI) m/z 357.1 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 11.54 (s, NH), 11.06 (s, NH), 8.13(s, 1H), 7.6 (s, 1H), 7.57-7.54 (m, 1H), 7.44 (d, J=15.6 Hz, 1H),7.13-7.10 (m, 1H), 7.05-7.02 (m, 1H), 6.69 (d, J=15.6 Hz, 1H), 4.67 (s,2H), 4.48-4.45 (m, 2H), 4.13-4.08 (m, 2H), 3.75-3.70 (m, 1H).

Example 47(E)-6-(3-Oxo-3-(3-(3,3,3-trifluoropropoxy)azetidin-1-yl)prop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E47) Step 1: 1-Benzhydryl-3-(3,3,3-trifluoropropoxy)azetidine

A solution of 1-benzhydrylazetidin-3-yl methanesulfonate (500 mg, 1.57mmol) in trifluoroethanol (3.5 mL, 30.7 mmol) was stirred undermicrowaves at 110° C. for 30 minutes. The reaction mixture was dilutedby addition of dichloromethane (100 mL) and a saturated solution ofsodium hydrogencarbonate (25 mL). The aqueous layer was separated andextracted with dichloromethane (2×10 mL). The combined organic phase wasdried over sodium sulfate, filtered and concentrated to dryness. Theresidue was purified by chromatography on silica gel usingdichloromethane/ethyl acetate (90:10) as eluent. The title product wasobtained as a light yellow gum (170 mg, 32%).

LCMS (ESI-APCI) m/z 336.1 (M+H)⁺

Step 2: 3-(3,3,3-Trifluoropropoxy)azetidine hydrochloride

1-Chloroethyl chloroformate (136 μL, 1.25 mmol) was added to a solutionof 1-benzhydryl-3-(3,3,3-trifluoropropoxy)-azetidine (400 mg, 1.19 mmol)in dichloromethane (10 mL) at 0° C. The reaction mixture was stirred for1 hour. Ethanol (10 mL) was added and the reaction mixture was stirredfor 1 hour at room temperature and for 2 hours at 45° C. Afterconcentration to dryness, the crude mixture was triturated in petroleumether (2×20 mL) to give a yellow oil (245 mg, quantitative) which wasused in the next step without further purification.

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 9.25 (s, NH₂), 4.43-4.40 (m, 1H),4.13-4.09 (m, 2H), 3.80-3.77 (m, 2H), 3.61 (t, J=6.4 Hz, 2H), 2.65-2.55(m, 2H).

Step 3:(E)-6-(3-Oxo-3-(3-(3,3,3-trifluoropropoxy)azetidin-1-yl)prop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one

3-(3,3,3-Trifluoropropoxy)azetidine hydrochloride (194 mg, 0.94 mmol),EDCI (181 mg, 0.94 mmol), HOBt (128 mg, 0.94 mmol) anddiisopropylethylamine (274 μL, 1.57 mmol) were successively added to asolution of(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acidhydrochloride (160 mg, 0.63 mmol) in dimethylformamide (15 mL) at roomtemperature. The reaction mixture was stirred overnight then diluted byaddition of ethyl acetate (30 mL) and water (40 mL). The aqueous layerwas separated and extracted with ethyl acetate (2×30 mL). The combinedorganic phases were washed with a saturated solution of sodium chloride(3×30 mL), dried over sodium sulfate, filtered and concentrated todryness. The residue was purified by chromatography on silica gel usingdichloromethane/methanol (98:2) as eluent. The residue was finallyprecipitated from methanol to afford the title product as a white solid(90 mg, 39%).

LCMS (ESI-APCI) m/z 370.1 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 10.68 (s, NH), 8.34 (s, 1H), 8.02(s, 1H), 7.40 (d, J=15.6 Hz, 1H), 6.72 (d, J=15.6 Hz, 1H), 4.50-4.38 (m,2H), 4.18-4.07 (m, 2H), 3.76-3.72 (m, 1H), 3.63-3.59 (m, 2H), 2.91 (t,J=7.6 Hz, 2H), 2.5 (t, J=7.6 Hz, 2H), 2.63-2.51 (m, 2H). The CH₂ at 2.5ppm is partially hidden by DMSO.

Example 48(E)-6-(3-Oxo-3-(3-(4,4,4-trifluorobutoxy)azetidin-1-yl)prop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E48) Step 1: 1-Benzhydryl-3-(4,4,4-trifluorobutoxy)-azetidine

A suspension of 1-benzhydrylazetidin-3-yl methanesulfonate (247 mg, 0.78mmol) in trifluoropropanol (1 g, 7.8 mmol) was placed under micro-waveirradiations (100 W) and heated at 100° C. during 30 minutes. Thereaction mixture was diluted by addition of dichloromethane (50 mL) andwater (30 mL). The two phases were separated and the aqueous phase wasextracted with dichloromethane (2×20 mL). The combined organic phaseswere dried over sodium sulphate and concentrated to dryness. The residuewas purified by chromatography on silica gel using petroleum ether/ethylacetate (8:2) as eluent. The title product was isolated as a yellow oil(191 mg, 33%).

LCMS (ESI-APCI) m/z 350.2 (M+H)⁺

Step 2: 3-(4,4,4-Trifluorobutoxy)-azetidine hydrochloride

1-Chloroethyl chloroformate (65 μL, 0.60 mmol) was added to a solutionof 1-benzhydryl-3-(4,4,4-trifluorobutoxy)-azetidine (200 mg, 0.57 mmol)in dichloromethane (5 mL) at 0° C. The reaction mixture was stirred for3 hours and 30 minutes at room temperature. Ethanol (5 mL) was thenadded and the mixture was stirred for an additional 2 hours at 0° C. and2 hours at 70° C. The reaction mixture was concentrated under vacuum andthe residue was triturated in petroleum ether (2×20 mL) to give acolorless oil (130 mg, quantitative) which was used without furtherpurification.

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 9.14 (br s, NH₂), 4.36-4.32 (m, 1H),4.15-4.05 (m, 2H), 3.82-3.75 (m, 2H), 3.45-3.40 (m, 2H), 2.34-2.31 (m,2H), 1.74-1.70 (m, 2H).

Step 3:(E)-6-(3-Oxo-3-(3-(4,4,4-trifluorobutoxy)azetidin-1-yl)prop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one

3-(4,4,4-Trifluorobutoxy)-azetidine (129 mg, 0.59 mmol), EDCI (113 mg,0.59 mmol), HOBt (80 mg, 0.59 mmol) and diisopropylethylamine (170 μL,0.97 mmol) were successively added to a solution of(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acidhydrochloride (100 mg, 0.039 mmol) in dimethylformamide (10 mL) at roomtemperature. The reaction mixture was stirred overnight then dilutedwith ethyl acetate (50 mL) and water (50 mL). The aqueous layer wasseparated and extracted with ethyl acetate (2×50 mL). The combinedorganic phases were washed with a saturated solution of sodium chloride(3×100 mL), dried over sodium sulfate and concentrated to dryness. Theresidue was purified by chromatography on silica gel usingdichloromethane/methanol (95:5 to 9:1) as eluent. The residue wasfinally triturated in diethylether to give the title product as a paleyellow solid (52.5 mg, 35%).

LCMS (ESI-APCI) m/z 384.2 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 10.68 (s, NH), 8.34 (s, 1H), 8.01(s, 1H), 7.4 (d, J=15.6 Hz, 1H), 6.72 (d, J=15.6 Hz, 1H), 4.51-4.33 (m,2H), 4.17-4.07 (m, 2H), 3.77-3.73 (m, 1H), 3.46-3.42 (m, 2H), 2.92 (t,J=7.6 Hz, 2H), 2.5 (t, J=7.6 Hz, 2H), 2.36-2.29 (m, 2H), 1.79-1.24 (m,2H). The CH₂ at 2.5 ppm is partially hidden by DMSO.

Examples 49 and 506-((E)-3-(3-((E)-But-2-enyloxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E49) &6-((E)-3-(3-((Z)-But-2-enyloxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E50) Step 1: 1-Benzhydryl-3-(but-2-enyloxy)-azetidine

Sodium hydride (60% in oil, 160 mg, 4.17 mmol) was added to a solutionof 1-benzhydryl-3-azetidin-3-ol (500 mg, 2.09 mmol) in dimethylformamide(2 mL) at room temperature. The reaction mixture was stirred for 30minutes prior to the addition of crotyl bromide (430 μL, 4.17 mmol) insolution in dimethylformamide (3 mL). The reaction mixture was stirredat 80° C. overnight and cooled to room temperature. The mixture was thenpartitioned between ethyl acetate (30 mL) and water (50 mL). The aqueouslayer was separated and extracted with ethyl acetate (2×100 mL). Thecombined organic phases were washed with a saturated solution of sodiumchloride (3×100 mL), dried over sodium sulfate and concentrated todyness. The residue was purified by chromatography on silica gel usingdichloromethane/methanol (1:0 to 98:2) as eluent. The title product wasobtained as a yellow oil (292 mg, 74%, mixture of the 2 isomers).

LCMS (ESI-APCI) m/z 294.2 (M+H)⁺

Step 2: 3-(But-2-enyloxy)-azetidine hydrochloride

1-Chloroethylchloroformate (140 μL, 1.28 mmol) was added to a solutionof 1-benzhydryl-3-(but-2-enyloxy)-azetidine (290 mg, 0.98 mmol) indichloroethane (5 mL) at room temperature. The reaction mixture was thenheated up to 70° C. and stirred for 1 hour. After cooling down to roomtemperature, methanol (5 mL) was added and the reaction mixture wasstirred for an additional 1 hour at 70° C. After concentration todryness, the crude mixture was triturated in pentane (2×15 mL) to give ayellow solid (161 mg, quantitative) which was used in the next stepwithout further purification.

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 9.77 and 9.57 (br s, NH₂), 5.77-5.69(m, 1H), 5.51-5.46 (m, 1H), 4.46-4.42 (m, 1H), 4.17-4.12 (m, 2H),4.04-3.97 (m, 2H), 3.98 (d, J=6.2 Hz, 2H), 1.66 (d, J=6.2 Hz, 3H).

Step 3:6-((E)-3-(3-((E)-But-2-enyloxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one&6-((E)-3-(3-((Z)-But-2-enyloxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one

3-(But-2-enyloxy)-azetidine hydrochloride (129 mg, 0.79 mmol), EDCI (151mg, 0.79 mmol), HOBt (106 mg, 0.79 mmol) and diisopropylethylamine (230μL, 1.31 mmol) were successively added to a solution of(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acidhydrochloride (134 mg, 0.52 mmol) in dimethylformamide (13 mL) at roomtemperature. The reaction mixture was stirred overnight then diluted byaddition of ethyl acetate (50 mL) and a saturated solution of water (50mL). The aqueous layer was successively extracted with ethyl acetate(3×50 mL) and dichloromethane (3×50 mL). The combined organic phaseswere washed with a saturated solution of sodium chloride (3×50 mL),dried over sodium sulfate and concentrated to dryness. The residue waspurified by chromatography on silica gel using dichloromethane/methanol(1:0 to 95:5) as eluent. The 2 isomers were finally separated bypreparative HPLC to afford the trans-isomer (45 mg, 26%) and thecis-isomer (14 mg, 8%).

Trans-Isomer:

LCMS (ESI-APCI) m/z 328.2 (M+H)⁺

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 8.35 (s, 1H), 8.30 (s, 1H), 7.63 (s,1H), 7.58 (d, J=15.6 Hz, 1H), 6.41 (d, J=15.6 Hz, 1H), 5.81-5.72 (m,1H), 5.62-5.56 (m, 1H), 4.46-4.36 (m, 2H), 4.30-4.25 (m, 1H), 4.18-4.15(m, 1H), 4.03-3.99 (m, 1H), 3.91 (d, J=6.2 Hz, 2H), 3.02 (t, J=7.6 Hz,2H), 2.70 (t, J=7.6 Hz, 2H), 1.74 (d, J=6.2 Hz, 3H).

Cis-Isomer:

LCMS (ESI-APCI) m/z 328.2 (M+H)⁺

¹H NMR (CDCl3, 400 MHz): δ (ppm): 8.33 (s, 2H), 7.63 (s, 1H), 7.58 (d,J=15.6 Hz, 1H), 6.42 (d, J=15.6 Hz, 1H), 5.76-5.71 (m, 1H), 5.58-5.54(m, 1H), 4.45-4.38 (m, 2H), 4.32-4.27 (m, 1H), 4.21-4.17 (m, 1H),4.06-4.03 (m, 3H), 3.00 (t, J=7.6 Hz, 2H), 2.70 (t, J=7.6 Hz, 2H), 1.69(d, J=6.8 Hz, 3H).

Example 516-((E)-3-(3-((E)-2-methylbut-2-enyloxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E51) Step 1: (E)-2-Methylbut-2-en-1-ol

Sodium borohydride (1.08 g, 28.5 mmol) was added to a solution oftrans-2-methyl-2-butenal (2.0 g, 23.8 mmol) in methanol (10 mL) at 0° C.The reaction mixture was stirred for 1 hour then diluted by addition ofwater (10 mL) and ethyl acetate (15 mL). The aqueous layer was separatedand extracted with ethyl acetate (2×20 mL). The combined organic phaseswere washed with a saturated solution of sodium chloride (2×25 mL),dried over sodium sulfate, filtered and concentrated carefully todryness (volatile compound). The title product was obtained as acolorless oil (1.2 g, 60%).

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 5.46-5.42 (m, 1H), 3.42 (s, 2H), 1.87(s, OH), 1.62 (s, 3H), 1.57 (d, J=2 Hz, 3H).

Step 2: (E)-1-Benzhydryl-3-(2-methylbut-2-enyloxy)azetidine

A solution of 1-benzhydrylazetidin-3-yl methanesulfonate (447 mg, 1.41mmol) in (E)-2-methylbut-2-en-1-ol (1.2 g, 14.1 mmol) was stirred undermicrowaves at 110° C. for 30 minutes. After concentration to dryness,the residue was purified by chromatography on silica gel using petroleumether/ethyl acetate (9:1) as eluent. The title product was obtained as acolorless oil (290 mg, 67%).

LCMS (ESI-APCI) m/z 308.2 (M+H)⁺

Step 3: (E)-3-(2-Methylbut-2-enyloxy)azetidine hydrochloride

1-Chloroethyl chloroformate (107 μL, 1.0 mmol) was added to a solutionof (E)-1-benzhydryl-3-(2-methylbut-2-enyloxy)azetidine (290 mg, 0.941mmol) in dichloromethane (10 mL) at 0° C. The reaction mixture wasstirred for 2 hours. Ethanol (10 mL) was then added and the reactionmixture was stirred for an additional 2 hours at 0° C. and 16 hours atroom temperature. After concentration to dryness, the crude mixture wastriturated in pentane (5 mL) and petroleum ether (5 mL) to afford acolorless oil (211 mg, quantitative).

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 9.87 (br s, NH₂), 9.55 (br s, NH₂),5.52-5.45 (m, 1H), 4.43-4.37 (m, 1H), 4.16-4.12 (m, 2H), 4.02-4.0 (m,2H), 3.8 (s, 2H), 1.63-1.60 (m, 6H).

Step 4:6-((E)-3-(3-((E)-2-Methylbut-2-enyloxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one

(E)-3-(2-Methylbut-2-enyloxy)azetidine hydrochloride (168 mg, 0.94mmol), EDCI (182 mg, 0.94 mmol), HOBt (132 mg, 0.94 mmol) anddiisopropylethylamine (276 μL, 1.58 mmol) were successively added to asolution of(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acidhydrochloride (161 mg, 0.63 mmol) in dimethylformamide (12 mL) at roomtemperature. The reaction mixture was stirred overnight then diluted byaddition of ethyl acetate (40 mL) and water (40 mL). The aqueous layerwas separated and extracted with ethyl acetate (2×40 mL). The combinedorganic phases were washed with a saturated solution of sodium chloride(3×50 mL), dried over sodium sulfate, filtered and concentrated todryness. The residue was purified by chromatography on silica gel usingdichloromethane/methanol (98:2) as eluent. After trituration in diethylether, petroleum ether and methanol, the title product was obtained as awhite solid (46 mg, 21%).

LCMS (ESI-APCI) 342.2 m/z (M+H)+

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 10.68 (s, 1H), 8.37 (s, 1H), 8.04(s, 1H), 7.43 (d, J=16 Hz, 1H), 6.74 (d, J=16 Hz, 1H), 5.56-5.50 (m,1H), 4.51-4.46 (m, 1H), 4.36-4.33 (m, 1H), 4.17-4.08 (m, 2H), 3.84 (s,2H), 3.78-3.74 (m, 1H), 2.94 (t, J=7.6 Hz, 2H), 2.5 (t, J=7.6 Hz, 2H),1.64 (s, 3H), 1.63 (d, J=8 Hz, 3H). The CH₂ at 2.5 ppm is partiallyhidden by DMSO.

Example 52(E)-6-(3-(3-(Benzo[b]thiophen-2-ylmethoxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E52) Step 1: 2-(Bromomethyl)benzo[b]thiophene

HBr in acetic acid (6 mL) was added to a suspension ofbenzo[b]thiophen-2-ylmethanol (1 g, 6.1 mmol) in dichloromethane (6 mL)at room temperature. The reaction mixture was stirred for 3 hours thendiluted by addition of chloroform (20 mL). The organic phase was washedwith a saturated solution of hydrogenocarbonate (20 mL), dried oversodium sulfate and concentrated to dryness. The title product wasobtained as a yellow oil (1.3 g, quantitative).

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 7.91 (m, 1H), 7.83 (m, 1H), 7.53-7.45(m, 2H), 7.33 (s, 1H), 4.86 (s, 2H).

Step 2: 1-Benzhydryl-3-(benzo[b]thiophen-2-ylmethoxy)-azetidine

Sodium hydride (60% in oil, 243 mg, 6.0 mmol) was added to a solution of1-benzhydryl-3-azetidin-3-ol (727 mg, 3.0 mmol) in dimethylformamide (5mL) at room temperature. The reaction mixture was stirred for 30 minutesprior to the addition of a solution of 2-(bromomethyl)benzo[b]thiophene(1.38 g, 6 mmol) in dimethylformamide (5 mL). The reaction mixture wasstirred for 3 hours at room temperature. The reaction mixture was thendiluted by addition of ethyl acetate (30 mL) and water (30 mL). Theaqueous layer was separated and extracted with ethyl acetate (2×30 mL).The combined organic phases were washed with a saturated solution ofsodium chloride (3×50 mL), dried over sodium sulfate, filtered andconcentrated to dryness. The residue was purified by chromatography onsilica gel using petroleum ether/ethyl acetate (9:1 to 8:2) as eluent.The title product was obtained as a white solid (1.04 g, 85%).

LCMS (ESI-APCI) m/z 386.2 (M+H)⁺

Step 3: 3-(Benzo[b]thiophen-2-ylmethoxy)-azetidine hydrochloride

1-Chloroethyl chloroformate (322 μL, 1.1 mmol) was added to a solutionof 1-benzhydryl-3-(benzo[b]thiophen-2-ylmethoxy)-azetidine (1.04 g, 2.7mmol) in dichloromethane (17 mL) at room temperature. The reactionmixture was stirred for 2 hours. Methanol (17 mL) was added and thereaction mixture was stirred for an additional 16 hours at roomtemperature. The reaction mixture was then concentrated to dryness andthe residue was triturated in petroleum ether (20 mL) to afford thetitle compound as a yellow solid (600 mg, 90%).

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 8.92 (br s, NH), 8.77 (br s, NH),7.97-7.95 (m, 1H), 7.85-7.83 (m, 1H), 7.39-7.35 (m, 3H), 4.81 (s, 2H),4.53-4.56 (m, 1H), 4.14-4.09 (m, 2H), 3.88-8.84 (m, 2H).

Step 4:(E)-6-(3-(3-(Benzo[b]thiophen-2-ylmethoxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one

3-(Benzo[b]thiophen-2-ylmethoxy)-azetidine hydrochloride (136 mg, 0.76mmol), EDCI (146 mg, 0.76 mmol), HOBt (103 mg, 0.76 mmol) anddiisopropylethylamine (222 μL, 1.27 mmol) were successively added to asolution of(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acidhydrochloride (130 mg, 0.51 mmol) in dimethylformamide (10 mL) at roomtemperature. The reaction mixture was stirred for 3 days. The reactionmixture was then diluted by addition of ethyl acetate (50 mL) and water(50 mL). The aqueous phase was extracted with ethyl acetate (3×100 mL)and dichloromethane (3×100 mL). The combined organic phases were washedwith a saturated solution of sodium chloride (3×50 mL), dried oversodium sulfate and concentrated to dryness. The residue was purified bychromatography on silica gel using dichloromethane/methanol (1:0 to95:5) as eluent. After trituration in acetone and methanol, the titleproduct was obtained as a white solid (112 mg, 45%).

LCMS (ESI-APCI) m/z 420.2 (M+H)⁺

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 8.33 (s, 1H), 8.29 (s, 1H), 7.96-7.94(m, 1H), 7.84-7.81 (m, 1H), 7.43-7.34 (m, 4H), 7.71 (d, J=15.6 Hz, 1H),4.8 (s, 2H), 4.52-4.48 (m, 2H), 4.17-4.11 (m, 2H), 3.79-3.76 (m, 1H),2.99 (t, J=7.6 Hz, 2H), 2.69 (t, J=7.6 Hz, 2H).

Example 53(E)-6-(3-(3-((4-Bromothiophen-2-yl)methoxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E53) Step 1: 4-Bromothiophen-2-yl)methanol

Sodium borohydride (594 mg, 15.7 mmol) was added to a solution of2-bromothiophene carboxaldehyde (2.5 g, 13 mmol) in a mixturetoluene/ethanol (16 mL, 1:1) at 0° C. The reaction mixture was stirredfor 2 hours at room temperature then partitioned between water (20 mL)and ethyl acetate (20 mL). The aqueous phase was separated and extractedwith ethyl acetate (2×30 mL). The combined organic phases were washedwith a saturated solution of sodium chloride (2×20 mL), dried oversodium sulphate, filtered and concentrated to dryness. The residue waspurified by chromatography on silica gel using petroleum ether/ethylacetate (7:3) as eluent. The title product was obtained as a white solid(2.47 g, 98%).

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 7.21 (d, J=1.2 Hz, 1H), 6.88 (d, J=1.2Hz, 1H), 4.75 (d, J=6 Hz, 2H).

Step 2: 4-Bromo-2-(chloromethyl)thiophene

Thionyl chloride (1.12 mL, 15.3 mmol) was added to a solution of4-bromothiophen-2-yl)methanol (2.47 g, 12.8 mmol) in dichloromethane (25mL) at 0° C. The reaction mixture was stirred for 2 h30 at roomtemperature. The reaction mixture was then diluted by addition of water(20 mL) and dichloromethane (20 mL). The aqueous phase was separated andthe organic phase was washed with a saturated solution of sodiumchloride (20 mL), dried over sodium sulphate, filtered and concentratedto dryness. The title product was obtained as a yellow oil (2.57 g, 95%)and used without further purification.

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 7.20 (s, 1H), 7.00 (s, 1H), 4.72 (s,2H).

Step 3: 1-Benzhydryl-3-((4-bromothiophen-2-yl)methoxy)-azetidine

Sodium hydride (60% in oil, 167 mg, 4.18 mmol) was added to a solutionof 1-benzhydryl-3-azetidin-3-ol (500 mg, 2.09 mmol) in dimethylformamide(10 mL) at room temperature. The reaction mixture was stirred for 30minutes prior to the addition of a solution of4-bromo-2-(chloromethyl)thiophene (884 mg, 4.18 mmol) indimethylformamide (3 mL). The reaction mixture was stirred overnight andthen diluted by addition of ethyl acetate (30 mL) and water (30 mL). Theaqueous layer was separated and extracted with ethyl acetate (3×30 mL).The combined organic phases were washed with a saturated solution ofsodium chloride (3×30 mL), dried over sodium sulfate, filtered andconcentrated to dryness. The residue was purified by chromatography onsilica gel using petroleum ether/ethyl acetate (95:5) as eluent. Thetitle product was obtained as a yellow solid (793 mg, 92%).

LCMS (ESI-APCI) m/z 414.1; 416.1 (M+H)⁺

Step 4: 3-((4-Bromothiophen-2-yl)methoxy)-azetidine hydrochloride

1-Chloroethyl chloroformate (218 μL, 2.0 mmol) was added to a solutionof 1-benzhydryl-3-((4-bromothiophen-2-yl)methoxy)-azetidine (793 mg,1.91 mmol) in dichloromethane (10 mL). The reaction mixture was stirredfor 1 hour at 0° C. and for an additional 1 hour at room temperature.Ethanol (10 mL) was then added and the reaction mixture was stirredovernight. After concentration to dryness, the crude mixture wasprecipitated from a mixture dichloromethane/diethyl ether to afford awhite solid (417 mg, 77%) which was used in the next step withoutfurther purification.

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 8.81 (br s, NH₂), 7.72 (s, 1H), 7.18(s, 1H), 4.68 (s, 2H), 4.49-4.44 (m, 1H), 4.14-4.10 (m, 2H), 3.87-3.82(m, 2H)

Step 5:(E)-6-(3-(3-((4-Bromothiophen-2-yl)methoxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one

3-((4-Bromothiophen-2-yl)methoxy)-azetidine hydrochloride (168 mg, 0.59mmol), EDCI (113 mg, 0.59 mmol), HOBt (82 mg, 0.59 mmol) anddiisopropylethylamine (171 μL, 1.00 mmol) were successively added to asolution of(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acidhydrochloride (100 mg, 0.39 mmol) in dimethylformamide (10 mL) at roomtemperature. The reaction mixture was stirred overnight then diluted byaddition of ethyl acetate (40 mL) and water (40 mL). The aqueous phasewas separated and extracted with ethyl acetate (2×40 mL). The combinedorganic phases were washed with a saturated solution of sodium chloride(3×40 mL), dried over sodium sulfate, filtered and concentrated todryness. The residue was triturated in diethyl ether to afford a paleyellow solid (109 mg, 62%).

LCMS (ESI-APCI) m/z 448.1; 450.0 (M+H)⁺

¹H NMR (CDCl3, 400 MHz): δ (ppm): 8.39 (s, 1H), 8.30 (s, 1H), 7.64 (s,1H), 7.58 (d, J=15.6 Hz, 1H), 7.23 (d, J=1.2 Hz, 1H), 6.95 (d, J=1.2 Hz,1H), 6.39 (d, J=15.6 Hz, 1H), 4.63 (m, 2H), 4.47-4.43 (m, 2H), 4.29-4.26(m, 1H), 4.19-4.16 (m, 1H), 4.04-4.00 (m, 1H), 3.00 (t, J=7.6 Hz, 2H),2.70 (t, J=7.6 Hz, 2H).

Example 54(E)-6-(3-(3-((4-Chlorothiophen-2-yl)methoxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E54) Step 1: (4-Chlorothiophen-2-yl)methanol

Lithium aluminium hydride (117 mg, 3.08 mmol) was added to a solution of2-chlorothiophene carboxylique acid (500 mg, 3.08 mmol) intetrahydrofuran (5 mL) at 0° C. The reaction mixture was stirred for 1hour at room temperature and then diluted by addition of water (10 mL)and an aqueous solution of sodium hydroxide (1N, 10 mL). The aqueoussolution was extracted with ethyl acetate (2×30 mL). The combinedorganic phases were dried over sodium sulphate, filtered andconcentrated to dryness. The residue was purified by chromatography onsilica gel using petroleum ether/ethyl acetate (9:1) as eluent. Thetitle product was obtained as a white solid (330 mg, 72%).

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 7.05 (d, J=1.6 Hz, 1H), 6.88 (d, J=1.6Hz, 1H), 4.78 (s, 2H).

Step 2: 4-Chloro-2-(chloromethyl)thiophene

Thionyl chloride (117 L, 1.60 mmol) in solution in dichloromethane (1mL) was added to a solution of (4-chlorothiophen-2-yl)methanol (140 mg,0.94 mmol) in dichloromethane (3 mL) at 0° C. The reaction mixture wasstirred for 2 h30 at room temperature then 30 minutes at 40° C. Thereaction mixture was diluted by addition of water (20 mL) anddichloromethane (20 mL). The organic phase was washed with a saturatedsolution of sodium chloride (20 mL), dried over sodium sulphate,filtered and concentrated to dryness. The title product was obtained asan orange oil (165 mg, 77%) and used in the next step without furtherpurification.

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 7.08 (d, J=1.6 Hz, 1H), 6.96 (d, J=1.6Hz, 1H), 4.69 (s, 2H).

Step 3: 1-Benzhydryl-3-((4-chlorothiophen-2-yl)methoxy)-azetidine

Sodium hydride (60% in oil, 167 mg, 4.18 mmol) was added to a solutionof 1-benzhydryl-3-azetidin-3-ol (500 mg, 2.09 mmol) in dimethylformamide(10 mL) at room temperature. The reaction mixture was stirred for 30minutes prior to the addition of a solution of4-chloro-2-(chloromethyl)thiophene (884 mg, 4.18 mmol) indimethylformamide (3 mL). The reaction mixture was then stirredovernight. The reaction mixture was diluted by addition of ethyl acetate(30 mL) and water (30 mL). The aqueous layer was separated and extractedwith ethyl acetate (3×30 mL). The combined organic phases were washedwith a saturated solution of sodium chloride (3×30 mL), dried oversodium sulfate, filtered and concentrated to dryness. The residue waspurified by chromatography on silica gel using petroleum ether/ethylacetate (95:5) as eluent. The title product was obtained as a yellowsolid (793 mg, 92%).

LCMS (ESI-APCI) m/z 414.1; 416.1 (M+H)⁺

Step 4: 3-((4-Chlorothiophen-2-yl)methoxy)-azetidine hydrochloride

1-Chloroethyl chloroformate (218 μL, 2.0 mmol) was added to a solutionof 1-benzhydryl-3-((4-chlorothiophen-2-yl)methoxy)-azetidine (793 mg,1.91 mmol) in dichloromethane (10 mL) at 0° C. The reaction mixture wasstirred for 1 hour at 0° C. and for an additional 1 hour at roomtemperature. Ethanol (10 mL) was added and the reaction mixture wasstirred overnight. After concentration to dryness, the crude mixture wasprecipitated from a mixture dichloromethane/diethyl ether to afford thetitle compound as a white solid (417 mg, 77%) which was used withoutfurther purification.

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 8.81 (br s, NH₂), 7.72 (s, 1H), 7.18(s, 1H), 4.68 (s, 2H), 4.49-4.44 (m, 1H), 4.14-4.10 (m, 2H), 3.87-3.82(m, 2H).

Step 5:(E)-6-(3-(3-((4-Chlorothiophen-2-yl)methoxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one

3-((4-Chlorothiophen-2-yl)methoxy)-azetidine hydrochloride (141 mg, 0.59mmol), EDCI (113 mg, 0.59 mmol), HOBt (82 mg, 0.59 mmol) anddiisopropylethylamine (171 μL, 1.00 mmol) were successively added to asolution of(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acidhydrochloride (100 mg, 0.39 mmol) in dimethylformamide (6 mL) at roomtemperature. The reaction mixture was stirred overnight and then dilutedby addition of ethyl acetate (40 mL) and water (40 mL). The aqueousphase was extracted with ethyl acetate (2×40 mL). The combined organicphases were washed with a saturated solution of sodium chloride (3×40mL), dried over sodium sulfate, filtered and concentrated to dryness.The residue was triturated in diethyl ether to afford the title compoundas a pale yellow solid (37 mg, 23%).

LCMS (ESI-APCI) m/z 404.1 (M+H)⁺

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 8.30 (s, 1H), 8.19 (s, 1H), 7.62 (s,1H), 7.58 (d, J=15.6 Hz, 1H), 7.11 (d, J=1.4 Hz, 1H), 6.90 (d, J=1.4 Hz,1H), 6.39 (d, J=15.6 Hz, 1H), 4.64-4.60 (m, 2H), 4.46-4.42 (m, 2H),4.29-4.26 (m, 1H), 4.19-4.15 (m, 1H), 4.06-4.02 (m, 1H), 2.99 (t, J=7.2Hz, 2H), 2.7 (m, J=7.2 Hz, 2H).

Example 556-((E)-3-Oxo-3-(3-((Z)-1-(propoxyimino)ethyl)azetidin-1-yl)prop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E55) Step 1: Azetidine-1,3-dicarboxylic acid mono-tert-butyl ester

Di-tert-buyldicarbonate (2.5 g, 11.88 mmol) was added to a stirredsolution of 3-azetidinecarboxylic acid (1.0 g, 9.9 mmol) in a mixture ofTHF/water (12 mL:2 mL) and 1M KOH (1 mL) at room temperature. Thereaction mixture was stirred for 16 hours and then concentrated todryness. The crude was partitioned between an aqueous solution of 1NNaOH (10 mL) and diethyl ether (50 mL). The ether layer was discardedand the aqueous layer was acidified with a 3M aqueous solution of KHSO₄until pH=2 and extracted with diethyl ether (3×100 ml). The combinedorganic phases were washed with brine, dried over magnesium sulfate andconcentrated in vacuo to give the title compound as a white solid (1.4g, 70%).

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.64 (s, 1H), 4.02-3.93 (m, 2H),3.87-3.80 (m, 2H), 3.36-3.27 (m, 1H), 1.36 (s, 9H).

Step 2:3-(2,2-Dimethyl-4,6-dioxo-[1,3]dioxane-5-carbonyl)-azetidine-1-carboxylicacid tert-butyl ester

Meldrum's acid (0.85 g, 5.97 mmol), DCC (1.22 g, 5.97 mmol), and DMAP(1.45 g, 11.94 mmol) were successively added to a solution ofazetidine-1,3-dicarboxylic acid mono-tert-butyl ester (1.2 g, 5.97 mmol)in dichloromethane (25 mL) at room temperature. The reaction mixture wasstirred overnight and then diluted by addition of cyclohexane (25 mL).The precipitate of dicyclohexyl urea was then filtered and rinsed withdiethyl ether (100 mL). The mother liquors were diluted with DCM (100mL) and washed with a 1M solution of aqueous HCl (2×30 mL), dried oversodium sulfate, filtered and concentrated to dryness. After triturationin diethyl ether the title compound was obtained as a white solid (1.9g, 100%).

¹H NMR (400 MHz, CDCl₃) δ (ppm): 4.52-4.48 (m, 1H), 4.25-4.20 (t, 2H),4.12-4.07 (m, 2H), 3.36-3.27 (m, 1H), 1.71 (s, 6H), 1.41 (s, 9H).

Step 3: 3-Acetyl-azetidine-1-carboxylic acid tert-butyl ester

A solution of3-(2,2-dimethyl-4,6-dioxo-[1,3]dioxane-5-carbonyl)-azetidine-1-carboxylicacid tert-butyl ester (1.0 g, 3.05 mmol) in a mixture of actic acid (0.5mL), water 0.25 mL and dioxane (3 mL) was stirred under microwaves at100° C. for 30 minutes. After concentration to dryness, the residue wascoeveoparted with dichloromethane (2×100 mL). The title product wasobtained as a colorless gum (600 mg, 100%).

LCMS (ESI-APCI) m/z 308.2 (M+H)⁺

Step 4: 1-Azetidin-3-yl-ethanone TFA

Trifluoroacetic acid (8 mL) was added to a suspension of3-acetyl-azetidine-1-carboxylic acid tert-butyl ester (800 mg, 4.0 mmol)in dichloromethane (20 mL). The reaction mixture was stirred at roomtemperature for 4 hours and concentrated to dryness to afford the titleproduct as a colorless gum (800 mg, 100%).

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 4.02-4.06 (m, 4H), 3.75-3.80 (m, 1H),2.13 (s, 3H).

Step 5:6-[3-(3-Acetyl-azetidin-1-yl)-3-oxo-propenyl]-3,4-dihydro-1H-[1,8]naphthyridin-2-one

1-Azetidin-3-yl-ethanone TFA (700 mg, 3.54 mmol), EDCI (676 mg, 3.54mmol), HOBt (477 mg, 3.54 mmol) and diisopropylethylamine (2.1 mL, 11.8mmol) were successively added to a solution of(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acidhydrochloride (600 mg, 2.36 mmol) in dimethylformamide (15 mL) at roomtemperature. The reaction mixture was stirred overnight. The reactionmixture was then diluted by addition of ethyl acetate (40 mL) and water(40 mL). The organic layer was discarded and the aqueous layer wasbasified with an aqueous solution of saturated sodium carbonate untilpH=12 and finally extracted with ethyl acetate (2×50 mL). The combinedorganic phases were washed with a saturated solution of sodium chloride(3×50 mL), dried over sodium sulfate and concentrated to dryness. Theresidue was purified by chromatography on silica gel usingdichloromethane/methanol (1:0 to 95:5) as eluent to obtain the titlecompound as a white solid (354 mg, 50%).

LCMS (ESI-APCI) m/z 390.1 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm): 10.64 (s, 1H), 8.34 (d, 1H), 8.01(s, 1H), 7.41-7.37 (d, 1H), 6.72-6.68 (d, 2H), 4.33-4.44 (m, 2H),4.05-4.09 (m, 1H), 3.96-3.99 (m, 1H), 3.62-3.66 (m, 1H), 3.31-3.51 (m,1H), 2.89-2.92 (t, 3H), 2.50 (t, 2H), 2.16 (s, 3H)

Step 6:6-((E)-3-Oxo-3-(3-((Z)-1-(propoxyimino)ethyl)azetidin-1-yl)prop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one

1-(Amino-oxy)-propane hydrochloride (32 mg, 0.29 mmol) was added to asolution of(E)-6-(3-(3-acetylazetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one(61.3 mg, 0.20 mmol) in a mixture methanol/dichloromethane (8:2, 3.5 mL)at room temperature. The reaction mixture was stirred overnight. Afterconcentration to dryness, the residue was purified by chromatography onsilica gel using dichloromethane/methanol (95:5) as eluent. The titleproduct was obtained as a white solid (56.0 mg, 76%).

HPLC isomer ratio 86:14, geometry not assigned (the minor isomer has theshortest retention time).

LCMS (ESI-APCI) m/z 357.2 (M+H)⁺

¹H NMR (DMSO-d₆, 400 MHz) (mixture of 2 isomers): δ (ppm): 10.64 (s,1H), 8.35 (s, 1H), 8.03 (s, 1H), 7.40 (d, J=15.6 Hz, 1H), 6.72 (d,J=15.6 Hz, 1H), 4.45-4.33 (m, 2H), 4.13-4.10 (m, 1H), 3.99-3.94 (m, 3H),3.48-3.44 (m, 1H), 2.92 (t, J=7.2 Hz, 2H), 2.54 (t, J=7.2 Hz, 2H),1.96-1.84 (s, 3H), 1.65-1.57 (m, 2H), 0.92-0.86 (m, 3H). The CH₂ at 2.5ppm is partially hidden by DMSO.

Example 566-((E)-3-Oxo-3-(3-((Z)-1-(2,2,2-trifluoroethoxyimino)ethyl)azetidin-1-yl)prop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E56)

2,2,2-Trifluoroethoxyamine hydrochloride (37 mg, 0.24 mmol) was added toa solution of(E)-6-(3-(3-acetylazetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one(50 mg, 0.16 mmol) in methanol (4 mL). The reaction mixture was stirredat room temperature for 3 hours. After concentration to dryness theresidue was diluted by addition of dichloromethane (50 mL) and saturatedsodium bicarbonate solution (10 mL). The aqueous phase was extractedwith dichloromethane (2×40 mL). The combined organic phases were washedwith a saturated solution of sodium chloride (1×20 mL), dried oversodium sulfate, filtered and concentrated to dryness. The residue waspurified by chromatography on silica gel using ethyl acetate/methanol(95:5) as eluent to obtain the title product as a white solid (47 mg,50%).

HPLC isomer ratio 90:10, geometry not assigned (the minor isomer has theshortest retention time).

LCMS (ESI-APCI) m/z 397.1 (M+H)⁺

¹H NMR (CDCl₃, 400 MHz) (mixture of 2 isomers): δ (ppm): 8.31 (s, 1H),8.26 (s, 1H), 7.63 (s, 1H), 7.59 (d, J=15.6 Hz, 1H), 6.42 (d, J=15.6 Hz,1H), 4.46-4.39 (m, 2H), 4.33-4.28 (m, 2H), 4.16-4.11 (m, 2H), 3.50-3.41(m, 1H), 2.99 (t, J=7.6 Hz, 2H), 2.70 (t, J=7.6 Hz, 2H), 2.04-1.95 (s,3H).

Example 576-((E)-3-(3-((Z)-1-(Ethoxyimino)ethyl)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E57)

1-(Aminooxy)ethane hydrochloride (23 mg, 0.23 mmol) was added to asolution of(E)-6-(3-(3-acetylazetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one(50.0 mg, 0.16 mmol) in a mixture methanol/dichloromethane (8:2, 3.5 mL)at room temperature. The reaction mixture was stirred overnight. Afterconcentration to dryness, the residue was purified by chromatography onsilica gel using ethyl acetate/methanol (95:5) as eluent. The titleproduct was obtained as a white solid (20 mg, 35%).

HPLC isomer ratio 87:13, geometry not assigned (the minor isomer has theshortest retention time).

LCMS (ESI-APCI) m/z 343.1 (M+H)⁺

¹H NMR (CDCl₃, 400 MHz) (mixture of 2 isomers): δ (ppm): 8.45 (s, 1H),8.26 (s, 1H), 7.57 (s, 1H), 7.52 (d, J=15.6 Hz, 1H), 6.37 (d, J=15.6 Hz,1H), 4.39-3.99 (m, 6H), 3.39-3.37 (m, 1H), 2.93 (t, J=7.2 Hz, 2H), 2.63(t, J=7.2 Hz, 2H), 1.94-1.83 (s, 3H), 1.22-1.15 (m, 3H).

Example 58(E)-6-(3-(3-(Benzofuran-3-yl)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E58) Step 1: 1-Benzhydrylazetidin-3-one

Triethylamine (29.1 mL, 209 mmol) and a solution of sulphur trioxidepyridine complex (21.3 g, 134 mmol) in DMSO (100 mL) were added at 10°C. to a solution of 1-benzhydrylazetidin-3-ol (5.0 g, 20.9 mmol) in DMSO(60 mL). The resulting mixture was stirred at 10° C. for 45 minutes,then at room temperature for 4 hours, subsequently quenched by pouringonto crushed ice (˜200 g) and extracted with ethyl acetate (3×200 mL).The combined organic layers were washed with water (400 mL) and brine(400 mL), dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by column chromatography onsilica gel using petroleum ether/ethyl acetate (80:20 to 70:30) aseluent. The title product was obtained as a yellowish solid (4.35 g,88%).

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 7.50-7.20 (m, 10H), 4.60 (s, 1H), 4.01(s, 4H).

Step 2: 1-Benzhydryl-3-(benzofuran-3-yl)azetidin-3-ol

A 2.5 M solution of n-butyllithium in hexanes (3.25 mL, 8.13 mmol) wasadded dropwise to a solution of 3-bromobenzofuran (1.0 g, 5.08 mmol) indiethyl ether (22 mL) at −78° C. The reaction mixture was stirred for 20minutes at −78° C. and then a solution of 1-benzhydrylazetidin-3-one(1.2 g, 5.08 mmol) in diethyl ether (10 mL) was added dropwise at thesame temperature. The mixture was stirred for 15 minutes at −78° C.,then allowed to warm back to room temperature and stirred for 2 hours.Water (30 mL) was added and the mixture was extracted with ethyl acetate(3×30 mL). The combined organic layers were dried over sodium sulfate,filtered and concentrated. The crude residue was combined with anothercrude mixture which was obtained in the same manner from3-bromobenzofuran (500 mg, 0.25 mmol). The combined crude materials werepurified by chromatography on silica gel using petroleumether/dichloromethane (50:50 to 0:100) as eluent. The title compound wasobtained as a yellow sticky solid (761 mg, 40%).

LCMS (ESI-APCI) m/z 356.2 (M+H)⁺.

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 7.91 (d, J=7.2 Hz, 1H), 7.66 (s, 1H),7.52-7.13 (m, 13H), 4.53 (s, 1H), 3.73 (d, J=8.8 Hz, 2H), 3.43 (d, J=8.8Hz, 2H), 2.42 (br s, 1H).

Step 3: 1-Benzhydryl-3-(benzofuran-3-yl)-3-chloroazetidine

To a solution of 1-benzhydryl-3-(benzofuran-3-yl)azetidin-3-ol (760 mg,2.14 mmol) in dichloromethane (10 mL) was added at 0° C. triethylamine(387 μL, 2.78 mmol) and then dropwise a solution of methanesulfonylchloride (216 μL, 2.78 mmol) in dichloromethane (3 mL). The reactionmixture was stirred for 1 hour at room temperature, then diluted withwater (50 mL) and extracted with dichloromethane (3×50 mL). The combinedorganic layers were dried over sodium sulfate, filtered and concentratedto dryness. The crude title compound was obtained as a yellow gum (873mg, 109%) and used for the next step without further purification.

LCMS (ESI-APCI) m/z 374.1 (M+H)⁺.

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 7.77 (d, J=8.0 Hz, 1H), 7.65 (s, 1H),7.57-7.17 (m, 13H), 4.58 (s, 1H), 3.92-3.86 (m, 4H).

Step 4: 1-Benzhydryl-3-(benzofuran-3-yl)azetidine

A mixture of 1-benzhydryl-3-(benzofuran-3-yl)-3-chloroazetidine asobtained in the previous step (873 mg, 2.14 mmol), triethylamine (299μL, 2.14 mmol) and 10% palladium on carbon (227 mg) in ethyl acetate (15mL) and ethanol (15 mL) was stirred at room temperature under hydrogenatmosphere (˜1 atm) for 3 days. After removal of hydrogen, the mixturewas diluted with dichloromethane (100 mL), filtered through Clarcel® andconcentrated. The residue was taken up in dichloromethane (50 mL) andwashed with aqueous saturated sodium hydrogencarbonate (50 mL). Theaqueous layer was back-washed with dichloromethane (2×50 mL) and all thecombined organic layers were dried over sodium sulfate, filtered andconcentrated. The residue was purified by chromatography on silica gelusing petroleum ether/ethyl acetate (100:0 to 95:5) as eluent followedby preparative TLC on reversed phase C18 using acetonitrile/water(90:10) as eluent. The title compound was obtained as a yellow gum (52mg, 7%).

LCMS (ESI-APCI) m/z 340.2 (M+H)⁺.

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 7.68 (d, J=7.6 Hz, 1H), 7.47-7.17 (m,14H), 4.45 (s, 1H), 3.84-3.76 (m, 1H), 3.72-3.68 (m, 2H), 3.27-3.23 (m,2H).

Step 5: 3-(Benzofuran-3-yl)azetidine hydrochloride

1-Chloroethyl chloroformate (18 μL, 0.16 mmol) was added to a solutionof 1-benzhydryl-3-(benzofuran-3-yl)azetidine (52 mg, 0.15 mmol) indichloromethane (1.5 mL) at 0° C. The reaction mixture was stirred for15 minutes at 0° C. and for 4 hours at room temperature. An additionalamount of 1-chloroethyl chloroformate (8 μL, 0.07 mmol) was added andstirring continued for 1 hour at room temperature. Ethanol (1.5 mL) wasadded and the reaction mixture was stirred for 3 days at roomtemperature. After concentration to dryness, the crude mixture wastriturated in n-pentane (2×2 mL) to afford the title compound as a pinksolid (42 mg, 130%) which was used without further purification.

LCMS (ESI-APCI) m/z 174.1 (M+H)⁺.

Step 6:(E)-6-(3-(3-(Benzofuran-3-yl)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one

A mixture of(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride (26 mg, 0.10 mmol), 3-(benzofuran-3-yl)azetidinehydrochloride as obtained in the previous step (42 mg, 0.15 mmol), EDCI(29.3 mg, 0.15 mmol), HOBt (20.7 mg, 0.15 mmol) anddiisopropylethylamine (105 μL, 0.61 mmol) in DMF (3 mL) was stirred atroom temperature for 19 hours, then diluted with water (15 mL) andextracted with ethyl acetate (3×15 mL). The combined organic phases werewashed with brine (3×50 mL), dried over sodium sulfate, filtered andconcentrated to dryness. The residue was purified by chromatography onsilica gel using dichloromethane/methanol (100:0 to 97:3) as eluent.After trituration in acetone (3×2 mL), co-evaporation withdichloromethane (3×2 mL) and vacuum-drying, the title compound wasobtained as an off-white solid (8 mg, 21%).

MS (ESI-APCI) m/z 374.1 (M+H)⁺.

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 8.32-8.31 (m, 1H), 8.05 (s, 1H),7.68-7.51 (m, 5H), 7.37-7.26 (m, 2H, overlapping with CDCl3), 6.49 (d,J=15.6 Hz, 1H), 4.78-4.74 (m, 1H), 4.62-4.57 (m, 1H), 4.49-4.46 (s, 1H),4.40-4.36 (m, 1H), 4.10-4.02 (m, 1H), 3.00 (t, J=7.6 Hz, 2H), 2.70 (t,J=7.6 Hz, 2H).

Example 59(E)-6-(3-(3-(Benzofuran-2-yl)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E59) Step 1: 1-Benzhydryl-3-(benzofuran-2-yl)azetidin-3-ol

A 2.5 M solution of n-butyllithium in hexanes (2.23 mL, 5.58 mmol) wasadded dropwise to a solution of 3-bromobenzofuran (1.0 g, 5.08 mmol) inTHF (35 mL) at −78° C. The reaction mixture was stirred for 30 minutesat −78° C. and then a solution of 1-benzhydrylazetidin-3-one (1.2 g,5.08 mmol, as prepared in step 1 of example FAB270) in THF (10 mL) wasadded dropwise at the same temperature. The mixture was allowed to warmback to room temperature overnight. Water (50 mL) was added and themixture was extracted with ethyl acetate (3×50 mL). The combined organiclayers were dried over sodium sulfate, filtered and concentrated. Theresidue was purified by chromatography on silica gel using petroleumether/dichloromethane (50:50 to 0:100) as eluent. The title compound wasobtained as a yellow solid (230 mg, 13%).

LCMS (ESI-APCI) m/z 356.2 (M+H)⁺.

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 7.60-7.17 (m, 14H), 6.79 (s, 1H), 4.58(s, 1H), 3.82-3.72 (m, 2H), 3.55-3.45 (m, 2H), 2.95 (br s, 1H).

Step 2: 1-Benzhydryl-3-(benzofuran-2-yl)-3-chloroazetidine

To a solution of 1-benzhydryl-3-(benzofuran-2-yl)-3-chloroazetidine (400mg, 1.13 mmol) and triethylamine (204 μL, 1.46 mmol) in dichloromethane(5 mL) was added at 0° C. dropwise a solution of methanesulfonylchloride (114 μL, 1.46 mmol) in dichloromethane (1.6 mL). The reactionmixture was stirred for 1 hour at room temperature, then diluted withwater (30 mL) and extracted with dichloromethane (3×30 mL). The combinedorganic layers were dried over sodium sulfate, filtered and concentratedto dryness. The crude title compound was obtained as a yellow solid (430mg, 102%) and used without further purification.

LCMS (ESI-APCI) m/z 374.1 (M+H)⁺.

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 7.58-7.10 (m, 14H), 6.77 (s, 1H), 4.57(s, 1H), 3.98-3.92 (m, 2H), 3.79-3.73 (m, 2H).

Step 3: 1-Benzhydryl-3-(benzofuran-2-yl)azetidine

A mixture of 1-benzhydryl-3-(benzofuran-2-yl)-3-chloroazetidine (458 mg,1.23 mmol) and 10% palladium on carbon (130 mg) in ethyl acetate (6 mL)and ethanol (6 mL) was stirred at room temperature under hydrogenatmosphere (˜1 atm) for 1 day. An additional amount of 10% palladium oncarbon (130 mg) was added as well as triethylamine (171 μL, 1.23 mmol)and hydrogenation was continued under same conditions for 3 days. Afterremoval of hydrogen, the mixture was diluted with dichloromethane (50mL), filtered through Clarcel® and concentrated. The residue was takenup in dichloromethane (30 mL) and washed with aqueous saturated sodiumhydrogencarbonate (30 mL). The aqueous layer was back-washed withdichloromethane (2×30 mL) and all the combined organic layers were driedover sodium sulfate, filtered and concentrated. The residue was purifiedby chromatography on silica gel using petroleum ether/ethyl acetate(100:0 to 95:5) as eluent. The title compound was obtained as a yellowgum (111 mg, 27%).

LCMS (ESI-APCI) m/z 340.2 (M+H)⁺.

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 7.52-7.17 (m, 14H), 6.50 (s, 1H), 4.48(s, 1H), 3.91-3.59 (m, 3H), 3.40-3.28 (m, 2H).

Step 4: 3-(Benzofuran-2-yl)azetidine hydrochloride

1-Chloroethyl chloroformate (36 μL, 0.33 mmol) was added to a solutionof 1-benzhydryl-3-(benzofuran-2-yl)azetidine (108 mg, 0.32 mmol) indichloromethane (3 mL) at 0° C. The reaction mixture was stirred for 2hours at 0° C. and for 1 hour at room temperature. Ethanol (3 mL) wasadded at 0° C. and the reaction mixture was stirred for 2 hours at 0°C., for 19 hours at room temperature and for 4 hours at 40° C. Afterconcentration to dryness, the crude mixture was triturated in n-pentane(2×4 mL) to afford the title compound as a pink solid (82 mg, 123%)which was used without further purification.

LCMS (ESI-APCI) m/z 174.2 (M+H)⁺.

Step 5:(E)-6-(3-(3-(Benzofuran-2-yl)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one

A mixture of(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride (54 mg, 0.21 mmol), 3-(benzofuran-2-yl)azetidinehydrochloride as obtained in the previous step (82 mg, ≦0.32 mmol), EDCI(61 mg, 0.32 mmol), HOBt (43 mg, 0.32 mmol) and diisopropylethylamine(181 μL, 1.06 mmol) in DMF (6 mL) was stirred at room temperature for 19hours, then diluted with water (15 mL) and extracted with ethyl acetate(3×15 mL). The combined organic phases were washed with brine (45 mL),dried over sodium sulfate, filtered and concentrated to dryness. Theresidue was purified by chromatography on silica gel usingdichloromethane/methanol (100:0 to 97:3) as eluent, preparative TLC onsilica gel using ethyl acetate/methanol (90:10) as eluent and finallypreparative TLC on reversed phase C18 using acetonitrile/water (70:30)as eluent. After trituration in acetone (3×3 mL) and co-evaporation withdichloromethane (4×3 mL), the title compound was obtained as a beigesolid (15 mg, 19%).

MS (ESI-APCI) m/z 374.1 (M+H)⁺.

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 8.36-8.33 (m, 2H), 7.66-7.62 (m, 2H),7.54-7.45 (m, 2H), 7.30-7.20 (m, 2H, overlapping with CDCl3), 6.60 (s,1H), 6.48 (d, J=15.6 Hz, 1H), 4.69-4.65 (m, 1H), 4.55-4.49 (m, 2H),4.41-4.37 (s, 1H), 4.11-4.03 (m, 1H), 3.00 (t, J=7.6 Hz, 2H), 2.70 (t,J=7.6 Hz, 2H).

Example 60(E)-6-(3-(3-(Benzofuran-7-yloxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E60) Step 1: 1-Benzhydryl-3-(benzofuran-7-yloxy)-azetidine

Potassium carbonate (348 mg, 2.52 mmol) and benzofuran-7-ol (169 mg,1.26 mmol) were successively added to a solution of1-benzhydrylazetidin-3-yl methanesulfonate (400 mg, 1.26 mmol) in DMF (8mL). The reaction mixture was stirred overnight at 90° C. and thendiluted by addition of ethyl acetate (20 mL) and water (20 mL). Theaqueous phase was separated and extracted with ethyl acetate (4×50 mL).The combined organic phases were washed with a saturated solution ofsodium chloride (5×50 mL), dried over sodium sulfate, filtered andconcentrated to dryness. The residue was purified by chromatography onsilica gel using petroleum ether/dichloromethane (1:0 to 2:8 to 0:1) aseluent. The title product was obtained as a yellow oil (350 mg, 69%).

LCMS (ESI-APCI) m/z 356.2 (M+H)⁺

Step 2: 3-(Benzofuran-7-yloxy)-azetidine hydrochloride

1-Chloroethyl chloroformate (107 μL, 0.99 mmol) was added to a solutionof 1-benzhydryl-3-(benzofuran-7-yloxy)-azetidine (349 mg, 0.98 mmol) indichloromethane (10 mL) at 0° C. The reaction mixture was stirred for 4hours at room temperature. Ethanol (10 mL) was added and the reactionmixture was stirred for an additional 2 hours at room temperature and 3hours at 40° C. After concentration to dryness, the residue was taken ina mixture dichloromethane/diethyl ether to afford the title compound asa white solid (193 mg, 87%).

¹H NMR (CDCl₃, 400 MHz): 10.11 (s, NH₂), 9.98 (s, 1H), 7.60 (d, J=2 Hz,1H), 7.11 (t, J=2 Hz, 1H), 6.77 (d, J=2 Hz, 1H), 6.65 (d, J=7.6 Hz, 1H),5.41-5.34 (m, 1H), 4.55-4.49 (m, 2H), 4.42-4.35 (m, 2H).

Step 3:(E)-6-(3-(3-(Benzofuran-7-yloxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one

3-(Benzofuran-7-yloxy)-azetidine hydrochloride (190 mg, 0.84 mmol), EDCI(161 mg, 0.84 mmol), HOBt (113 mg, 0.84 mmol) and diisopropylethylamine(240 μL, 1.40 mmol) were successively added to a solution of(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acidhydrochloride (143 mg, 0.56 mmol) in dimethylformamide (14 mL) at roomtemperature. The reaction mixture was stirred overnight. The reactionmixture was then diluted by addition of ethyl acetate (40 mL) and water(40 mL). The aqueous phase was separated and extracted with ethylacetate (2×40 mL). The combined organic phases were washed with asaturated solution of sodium chloride (3×40 mL), dried over sodiumsulfate, filtered and concentrated to dryness. The residue was purifiedby chromatography on silica gel using dichloromethane/methanol (1:0 to95:5) as eluent. After trituration in diethyl ether and acetone, thetitle compound was obtained as a white solid (80 mg, 37%).

LCMS (ESI-APCI) m/z 390.1 (M+H)⁺

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 8.31 (s, 1H), 8.22 (s, 1H), 7.64 (s,1H), 7.63 (s, 1H), 7.62 (d, J=15.6 Hz, 1H), 7.28 (d, J=8 Hz, 1H), 7.15(t, J=7.6 Hz, 1H), 6.79 (s, 1H), 6.61 (d, 8 Hz, 1H), 6.45 (d, J=15.6 Hz,1H), 5.31-5.26 (m, 1H), 4.75-4.70 (m, 1H), 4.60-4.55 (m, 1H), 4.51-4.48(m, 1H), 4.35-4.31 (m, 1H), 3.00 (t, J=8 Hz, 2H), 2.70 (t, J=8 Hz, 2H).

Example 61

(E)-6-(3-(3-(Benzo[b]thiophen-3-yloxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E61)

Step 1′: Benzo[b]thiophen-3-ol

A solution of methyl 2-(methylthio)benzoate (4.0 g, 22.00 mmol) in THF(60 mL) was added to a solution of freshly prepared LDA (2M in THF, 17.5mL, 35 mmol) placed at −78° C. The reaction mixture was stirred for 1hour at −78° C., then overnight at room temperature. The reactionmixture was diluted by addition of a saturated solution of ammoniumchloride (50 mL). The aqueous phase was separated and extracted withethyl acetate (3×70 mL). The combined organic phases were washed with asaturated solution of sodium chloride (40 mL), dried over sodiumsulfate, filtered and concentrated to dryness. The residue was purifiedby chromatography on silica gel using petroleum ether/ethyl acetate(95:5 to 9:1) as eluent. The title product was obtained as a pink solid(1.74 g, 53%).

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 7.71 (d, J=8 Hz, 1H), 7.49 (t, J=8 Hz,1H), 7.38 (d, J=8 Hz, 1H), 7.17 (t, J=8 Hz, 1H), 3.73 (s, 2H).

Step 1: 1-Benzhydryl-3-iodoazetidine

Potassium iodide (530 mg, 3.14 mmol) was added to a solution of1-benzhydrylazetidin-3-yl methanesulfonate (500 mg, 1.57 mmol) in amixture of water (2.5 mL) and 1,2-dimethoxyethane (2.5 mL) at roomtemperature. The reaction mixture was then heated up to reflux andstirred for 3 hours. After cooling down to room temperature, thereaction mixture was diluted by addition of water (50 mL) and ethylacetate (50 mL). The aqueous phase was separated and extracted withethyl acetate (2×70 mL). The combined organic phases were washed with asaturated solution of sodium chloride (40 mL), dried over sodiumsulfate, filtered and concentrated to dryness. The title compound wasobtained as a yellow solid (550 mg, 100%).

LCMS (ESI-APCI) m/z 350.0 (M+H)⁺

Step 2: 1-Benzhydryl-3-(benzo[b]thiophen-3-yloxy)azetidine

Benzo[b]thiophen-3-ol (215 mg, 1.43 mmol) and potassium carbonate (237mg, 1.72 mmol) were successively added to a solution of1-benzhydryl-3-iodoazetidine (500 mg, 1.43 mmol) in a mixture of1,2-dimethoxyethane (12 mL) and water (6 mL) at room temperature. Thereaction mixture was then heated up to 95° C. and stirred for 3 hours.After cooling down to room temperature, the reaction mixture was dilutedby addition of water (50 mL) and ethyl acetate (50 mL). The aqueousphase was separated and extracted with ethyl acetate (5×50 mL). Thecombined organic phases were washed with a saturated solution of sodiumchloride (2×50 mL), dried over sodium sulfate, filtered and concentratedto dryness. The residue was purified by chromatography on silica gelusing petroleum ether/ethyl acetate (1:0 to 9:1) as eluent. The titlecompound was obtained as a yellow oil (220 mg, 21%).

LCMS (ESI-APCI) m/z 372.1 (M+H)⁺

Step 3: 3-(Benzo[b]thiophen-3-yloxy)azetidine hydrochloride

1-Chloroethyl chloroformate (67.3 μL, 0.621 mmol) was added to asolution of 1-benzhydryl-3-(benzo[b]thiophen-3-yloxy)azetidine (220 mg,0.592 mmol) in dichloromethane (5 mL) at 0° C. The reaction mixture wasstirred for 2 hours at 0° C. and for 5 hours at room temperature.Ethanol (5 mL) was added and the reaction mixture was stirred for 1 hourat 40° C. After concentration to dryness, the crude mixture wasprecipitated from a mixture dichloromethane/pentane to afford a paleorange solid (140 mg, quantitative) which was used without furtherpurification.

¹H NMR (DMSO-d6, 400 MHz): δ (ppm): 9.23 (s, 1H), 9.08 (s, 1H),7.96-7.63 (m, 1H), 7.79-7.77 (m, 1H), 7.47-7.42 (m, 2H), 6.80 (s, 1H),5.15-5.18 (m, 1H), 4.45-4.52 (m, 2H), 4.09-4.02 (m, 2H).

Step 4:(E)-6-(3-(3-(Benzo[b]thiophen-3-yloxy)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one

3-(benzo[b]thiophen-3-yloxy)azetidine hydrochloride (140 mg, 0.58 mmol),EDCI (111 mg, 0.48 mmol), HOBt (78 mg, 0.58 mmol) anddiisopropylethylamine (420 μL, 2.41 mmol) were successively added to asolution of(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acidhydrochloride (123 mg, 0.48 mmol) in dimethylformamide (10 mL) at roomtemperature. The reaction mixture was stirred overnight and then dilutedby addition of ethyl acetate (40 mL) and water (40 mL). The aqueousphase was extracted with ethyl acetate (2×40 mL). The combined organicphases were washed with a saturated solution of sodium chloride (3×40mL), dried over sodium sulfate, filtered and concentrated to dryness.The residue was purified by chromatography on silica gel usingdichloromethane/methanol (98:2 to 95:5) as eluent. The title product wasobtained as a white solid (52 mg, 26%).

LCMS (ESI-APCI) m/z 406.1 (M+H)⁺

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 8.32 (s, 1H), 8.23 (s, 1H), 7.83-7.76(m, 2H), 7.65-7.61 (m, 2H), 7.41-7.38 (m, 2H), 6.46 (d, J=15.6 Hz, 1H),6.13 (s, 1H), 5.17-5.13 (m, 1H), 4.75-4.71 (m, 1H), 4.61-4.56 (m, 1H),4.46-4.43 (m, 1H), 4.34-4.30 (m, 1H), 2.99 (t, J=7.6 Hz, 2H), 2.70 (t,J=7.6 Hz, 2H).

Example 62(E)-6-(3-Oxo-3-(3-(thiophen-2-ylthio)azetidin-1-yl)prop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E62) Step 1: 1-Benzhydryl-3-(thiophen-2-ylthio)-azetidine

Potassium hydroxide (141 mg, 2.52 mmol) and thiophene-2-thiol (292 mg,238 μL) were added to a solution of 1-benzhydrylazetidin-3-ylmethanesulfonate (400 mg, 1.26 mmol) solubilized in THF (7 mL). Thereaction mixture was stirred a first time under microwave irradiations(100 W) at 80° C. for 30 minutes. Potassium hydroxide (141 mg, 2.52mmol) and thiophene-2-thiol (292 mg, 238 μL) were added and the reactionmixture was stirred for a second time under microwave irradiations (100W) at 80° C. for 30 minutes. After concentration to dryness, the residuewas purified by chromatography on silica gel using petroleum ether/ethylacetate (1:0 to 9:1) as eluent. The title product was obtained as ayellow solid (160 mg, 37%).

LCMS (ESI-APCI) m/z 338.1 (M+H)⁺

Step 2: 3-(Thiophen-2-ylthio)-azetidine hydrochloride

1-Chloroethyl chloroformate (140 μL, 1.3 mmol) was added to a solutionof 1-benzhydryl-3-(thiophen-2-ylthio)-azetidine (340 mg, 1.00 mmol) indichloroethane (11 mL) at 0° C. The reaction mixture was stirred for 3hours at room temperature and for 2 hours at 70° C. Ethanol (11 mL) wasadded and the reaction mixture was stirred for an additional 2 days atroom temperature. After concentration to dryness, the residue wastriturated in pentane (2×20 mL) to afford a brown oil (171 mg, 81%)which was used in the next step without further purification.

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 9.87 and 8.44 (s, NH₂), 7.43-7.41 (m,2H), 7.02-7.00 (m, 1H), 4.16-4.13 (m, 2H), 4.04-4.02 (m, 1H), 3.94-3.90(m, 2H).

Step 3:(E)-6-(3-Oxo-3-(3-(thiophen-2-ylthio)azetidin-1-yl)prop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one

3-(Thiophen-2-ylthio)-azetidine hydrochloride (170 mg, 0.82 mmol), EDCI(157 mg, 0.82 mmol), HOBt (110 mg, 0.82 mmol) and diisopropylethylamine(240 μL, 1.36 mmol) were successively added to a solution of(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acidhydrochloride (139 mg, 0.55 mmol) in dimethylformamide (14 mL) at roomtemperature. The reaction mixture was stirred overnight and then dilutedby addition of ethyl acetate (40 mL) and water (40 mL). The aqueousphase was extracted with ethyl acetate (2×40 mL). The combined organicphases were washed with a saturated solution of sodium chloride (3×40mL), dried over sodium sulfate, filtered and concentrated to dryness.The residue was purified by chromatography on silica gel using petroleumether/ethyl acetate (1:0 to 95:5) as eluent. After trituration inacetone, the title product was obtained as a white solid (114 mg, 37%).

LCMS (ESI-APCI) m/z 372.1 (M+H)⁺

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 8.29 (s, 1H), 8.27 (s, 1H), 7.61 (s,1H), 7.55 (d, J=15.6 Hz, 1H), 7.44-4.72 (m, 1H), 7.23-7.21 (m, 1H),7.06-7.03 (m, 1H), 6.34 (d, J=15.6 Hz, 1H), 4.60-4.55 (m, 1H), 4.43-4.38(m, 1H), 4.27-4.22 (m, 1H), 4.12-4.06 (m, 1H), 3.96-3.87 (m, 1H), 2.99(t, J=7.2 Hz, 2H), 2.69 (t, J=7.2 Hz, 2H).

Example 63(E)-6-(3-(3-Butoxyazetidin-1-yl)-3-oxoprop-1-enyl)-1′-methyl-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one(E63)

3-Butoxyazetidine hydrochloride (33 mg, 0.20 mmol), EDCI (72 mg, 0.4mmol), HOBt (54 mg, 0.4 mmol) and diisopropylethylamine (116 μL, 0.66mmol) were successively added to a solution of(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acidhydrochloride (45 mg, 0.13 mmol) in dimethylformamide (5 mL) at roomtemperature. The reaction mixture was stirred overnight and then dilutedby addition of ethyl acetate (40 mL) and water (40 mL). The aqueousphase was extracted with ethyl acetate (2×40 mL). The combined organicphases were washed with a saturated solution of sodium chloride (3×40mL), dried over sodium sulfate, filtered and concentrated to dryness.The residue was purified by chromatography on silica gel usingdichloromethane/methanol (7:3 to 5:5) as eluent. After precipitation inDCM/Et₂O and triturations in acetone, the title product was obtained asa white solid (10 mg, 17%).

LCMS (ESI-APCI) m/z 413.3 (M+H)⁺

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 8.55 (s, 1H), 8.31 (s, 1H), 7.66 (s,1H), 7.58 (d, J=15.6 Hz, 1H), 6.43 (d, J=15.6 Hz, 1H), 4.46-3.98 (m,5H), 3.42-3.40 (m, 2H), 2.89 (s, 2H), 2.88-2.81 (m, 2H), 2.46-2.42 (m,2H), 2.44 (s, 3H), 2.06-2.02 (m, 2H), 1.78-1.74 (m, 2H), 1.61-1.56 (m,2H), 1.42-1.37 (m, 2H), 0.93 (t, J=5.2 Hz, 3H).

Example 641′-Methyl-6-((E)-3-oxo-3-(3-((E)-1-(benzyloxyimino)ethyl)azetidin-1-yl)prop-1-enyl)-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one(E64)

O-benzylhydroxylamine hydrochloride (13.5 mg, 0.08 mmol) was added to asolution of(E)-6-(3-(3-acetylazetidin-1-yl)-3-oxoprop-1-enyl)-V-methyl-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one(23.0 mg, 0.06 mmol) in methanol (1.5 mL) at room temperature. Thereaction mixture was stirred overnight. After concentration to dryness,the residue was purified by chromatography on silica gel usingdichloromethane/methanol (9:1) as eluent. The title product was obtainedas a pink solid (9 mg, 31%).

HPLC isomer ratio 88:12, the major isomer adopts an (E) configuration(determined by ¹HMR and selective NOE experiments).

LCMS (ESI-APCI) m/z 488.3 (M+H)⁺

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 8.34 (s, 1H), 8.30 (s, 1H), 7.67 (s,1H), 7.59 (d, J=15.6 Hz, 1H), 7.36-7.37 (m, 5H), 6.43 (d, J=15.6 Hz,1H), 5.10 (s, 2H), 4.44-4.12 (m, 4H), 3.47-3.43 (m, 1H), 2.89 (s, 2H),2.90-2.83 (m, 2H), 2.73-2.68 (m, 2H), 2.46 (s, 3H), 2.02-1.98 (m, 2H),1.93 (s, 3H), 1.76-1.72 (m, 2H).

Example 651′-Methyl-6-((E)-3-oxo-3-(3-((E)-1-(propoxyimino)ethyl)azetidin-1-yl)prop-1-enyl)-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one(E65) Step 1:(E)-6-(3-(3-Acetylazetidin-1-yl)-3-oxoprop-1-enyl)-1′-methyl-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one

1-(Azetidin-3-yl)ethanone hydrochloride (110 mg, 0.8 mmol), EDCI (153mg, 0.8 mmol), HOBt (108 mg, 0.8 mmol) and diisopropylethylamine (700μL, 4.0 mmol) were successively added to a solution of(E)-3-(V-methyl-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-6-yl)acrylicacid hydrochloride (136 mg, 0.4 mmol) in dimethylformamide (15 mL) atroom temperature. The reaction mixture was stirred overnight. Afterconcentration to dryness, the residue was purified by chromatography onsilica gel using dichloromethane/methanol/ammoniac (9:1:0.1) as eluent.Precipitation in a mixture DCM/pentane allowed isolation of the titleproduct as a yellow solid (44.6 mg, 29%).

LCMS (ESI-APCI) m/z 383.3 (M+H)⁺

Step 2:1′-Methyl-6-((E)-3-oxo-3-(3-((E)-1-(propoxyimino)ethyl)azetidin-1-yl)prop-1-enyl)-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one

1-(Aminooxy)propane hydrochloride (10.5 mg, 0.093 mmol) was added to asolution of(E)-6-(3-(3-acetylazetidin-1-yl)-3-oxoprop-1-enyl)-V-methyl-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one(20.0 mg, 0.052 mmol) in methanol/dichloromethane (1.5 mL, 9:1) at roomtemperature. The reaction mixture was stirred overnight. Afterconcentration to dryness, the residue was purified by chromatography onsilica gel using chloroforme/methanol (9:1) as eluent. Triturations inacetone allowed isolation of the title product as a white solid (9 mg,39%).

HPLC isomer ratio 89:11, geometry not assigned (the minor isomer has theshortest retention time).

LCMS (ESI-APCI) m/z 440.3 (M+H)⁺

¹H NMR (CDCl₃, 400 MHz) (mixture of 2 isomers): δ (ppm): 8.20 (s, 1H),7.95 (s, 1H), 7.65 (s, 1H), 7.52 (d, J=15.6 Hz, 1H), 6.39 (d, J=15.6 Hz,1H), 4.39-4.36 (m, 2H), 4.24-4.19 (m, 1H), 4.11-4.07 (m, 1H), 3.96-3.93(m, 2H), 3.41-3.28 (m, 5H), 2.88 (s, 2H), 2.72 (s, 3H), 2.44-2.40 (m,2H), 1.96-1.92 (m, 2H), 1.84 (s, 3H), 1.62-1.58 (m, 2H), 0.87 (t, J=7.2Hz, 3H).

Example 66(E)-1′-Methyl-6-(3-oxo-3-(3-(2-(thiophen-2-yl)ethoxy)azetidin-1-yl)prop-1-en-1-yl)-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one(E66)

3-(2-(Thiophen-2-yl)ethoxy)azetidine hydrochloride (0.377 g, 1.718mmol), EDCI.HCl (0.658 g, 3.44 mmol), 1-hydroxy-7-azabenzotriazole(0.468 g, 3.44 mmol) and N,N-diisopropylethylamine (0.980 mL, 5.73 mmol)were successively added to a solution of(E)-3-(V-methyl-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-6-yl)acrylicacid hydrochloride (0.387 g, 1.145 mmol) in dry DMF (25 mL) at roomtemperature. The reaction mixture was stirred during for 4 days and thendiluted by addition of EtOAc (40 mL) and water (40 mL). The aqueousphase was separated and extracted with EtOAc (2×40 mL). The combinedorganic phases were washed with brine (60 mL), dried over Na₂SO₄₁filtered and concentrated to dryness to yield a dark orange oil fromwhich some solids precipitated (0.7 g). The crude product was purifiedusing preparative LCMS (Waters X-Bridge 50×19 mm 5 μm ODB in combinationwith Waters X-Bridge guard 10×19 mm 5 μm, at 25 ml/min flow rate;detection of product by mass and UV signal; eluent 10 mM ammonia inmilliQ water to 10 mM ammonia in MeCN 5% to 95% gradient). Afterlyophilization, FAB306 was obtained as a tan powder (53 mg, 10%) whichwas still contaminated by a minor impurity. This material was stirred in10 ml Et₂O for 2 h, then filtered off and dried in an air stream toyield target FAB306 (22 mg, 4%), which was pure according to LCMS andNMR analysis.

LCMS (ESI⁺): 467.2 (M+H)⁺;

¹H-NMR (CDCl₃, 400 MHz): δ (ppm): 8.29 (d, J=2 Hz, 1H), 8.15 (br s, 1H),7.65 (d, J=2 Hz, 1H), 7.59 (d, J=15 Hz, 1H), 7.17 (dd, J=1 Hz, 5 Hz,1H), 6.95 (m, 1H), 6.87 (m, 1H), 6.42 (d, J=15 Hz), 4.45 (m, 1H), 4.38(m, 1H), 4.29 (m, 1H), 4.17 (m, 1H, 4.03 (m, 1H), 6.67 (m, 2H), 3.13 (t,J=4 Hz, 2H), 2.88 (s, 1H), 2.62 (m, 2H), 2.42 (m, 2H), 2.32 (s, 3H),2.08 (m, 2H), 1.5-1.7 (m, 2H+H₂O)

Example 67(E)-6-(3-(3-(3-Methylbenzofuran-2-yl)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E67) Step 1: 1-Benzhydrylazetidin-3-one

To a stirring solution of DMSO (12.45 ml, 176 mmol) in DCM (150 mL) at−78° C. under an argon atmosphere was added dropwise oxalyl chloride(8.61 mL, 100 mmol). After stirring for 30 minutes at −78° C., asolution of 1-benzhydrylazetidin-3-ol (20 g, 84 mmol) in DCM (75 mL) wasadded dropwise. The reaction mixture was stirred for 1 h at −78° C.before triethylamine (58.2 ml, 418 mmol) was added. The reaction mixturewas allowed to reach 0° C. and was quenched with saturated NH₄Cl (150mL), and then extracted with DCM (3×). The combined organic layers werewashed with water, brine, dried on Na₂SO₄ and concentrated to give crude1-benzhydrylazetidin-3-one (20.8 g, 105%) as a yellow solid.

LCMS (ESI⁺): m/z 238.2 (M+H)⁺

Step 2: 1-Benzhydryl-3-(3-methylbenzofuran-2-yl)azetidin-3-ol

A solution of 3-methylbenzofuran (550 mg, 4.16 mmol) in dry THF (17 mL)was cooled to −78° C. and LDA (1.8 M in THF/heptane/ethylbenzene) (2.8mL, 5.04 mmol) was added dropwise under N₂ over 5 min. After stirringfor 30 min, 1-benzhydrylazetidin-3-one (1.61 g, 6.78 mmol) was addedportionwise over 10 min. The reaction was stirred under N₂ at −78° C.for 15 min, and was then allowed to warm to rt and stirred for 1.5 h.The reaction was quenched with 0.5N HCl and extracted with EtOAc. Theorganic layer was washed with water and brine, dried on Na₂SO₄ andconcentrated. The residue was purified by flash chromatography(heptane/EtOAc, 5%->35%), yielding the product (472 mg, 31%) as a yellowoil.

LCMS (ESI⁺): m/z 370.2 (M+H)⁺

Step 3: 1-Benzhydryl-3-(3-methylbenzofuran-2-yl)azetidine

To a cooled (0° C.) solution of1-benzhydryl-3-(3-methylbenzofuran-2-yl)azetidin-3-ol (406 mg, 1.099mmol) in dichloromethane (50 mL) were added triethylsilane (1.775 mL,10.99 mmol) and trifluoroacetic acid (1.630 mL, 22.01 mmol). Thereaction mixture was warmed to rt and stirred for 23 h. After 18 h,boron trifluoride etherate (0.6 mL, 4.73 mmol) was added and thereaction was allowed to stir for an additional 5 h. The reaction mixturewas partitioned between sat. NaHCO₃ and DCM. The layers were separated,the organic layer was washed with sat. NaHCO₃ and brine, dried on Na₂SO₄and concentrated. The residue was purified by flash chromatography(heptane/EtOAc, 0%->30%), yielding the title product (244 mg, 63%) as anoff-white solid.

LCMS (ESI⁺): m/z 354.2 (M+H)⁺

Step 4: 3-(3-Methylbenzofuran-2-yl)azetidine hydrochloride

To a cooled (0° C.) solution of1-benzhydryl-3-(3-methylbenzofuran-2-yl)azetidine (52.0 mg, 0.147 mmol)in DCM (4 mL) under N₂ was added 1-chloroethyl chloroformate (18.0 μL,0.167 mmol) and the reaction was stirred at rt under N₂ for 4 h. Next,EtOH was added and the mixture was stirred under nitrogen at 50° C. for21 h. The mixture was concentrated in vacuo and the residue trituratedwith Et₂O (3×5 mL), yielding the title product (20.4 mg, 62%) as anoff-white solid.

LCMS (ESI⁺): m/z 188.2 (M+H)⁺

Step 5:(E)-6-(3-(3-(3-Methylbenzofuran-2-yl)azetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one

To a solution of 3-(3-methylbenzofuran-2-yl)azetidine hydrochloride(19.9 mg, 0.089 mmol) in DMF (2 mL) were added(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride (15.8 mg, 0.062 mmol), EDCI.HCl (19.9 mg, 0.104 mmol),HOAt (14.0 mg, 0.103 mmol) and N,N-diisopropylethylamine (58 μL, 0.339mmol). The reaction was stirred at rt for 21 h, after which the mixturewas partitioned between EtOAc and H₂O. The layers were separated and theaqueous layer extracted with EtOAc. The combined organic layers werewashed with brine (3×), dried with Na₂SO₄ and concentrated. The residuewas triturated twice with Et₂O and the dried to yield (the titlecompound (14.0 mg, 58%) as a pale orange solid.

LCMS (APCI⁺): m/z 388 (M+H)⁺

¹H-NMR (CDCl₃, 400 MHz): δ (ppm): 8.82 (br s, 1H), 8.38 (s, 1H), 7.66(m, 2H), 7.45 (m, 2H), 7.26 (m, 2H, partially overlapping with solventsignal), 6.51 (d, J=15.6 Hz, 1H), 4.62 (m, 2H), 4.45 (m, 2H), 4.12 (m,1H), 3.01 (t, J=7.6 Hz, 2H), 2.71 (t, J=7.6 Hz, 2H), 2.21 (s, 3H).

Example 68(E)-1′-Methyl-6-(3-(3-(3-methylbenzofuran-2-yl)azetidin-1-yl)-3-oxoprop-1-enyl)-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one(E68) Step 1: (E)-Ethyl3-(1′-methyl-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-6-yl)acrylate

To a suspension of (E)-ethyl3-(2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-6-yl)acrylate(99.8 mg, 0.316 mmol) in 1,2-dichloroethane (5 mL) were added sodiumtriacetoxyborohydride (139 mg, 0.656 mmol) and paraformaldehyde (21 mg,0.699 mmol). The reaction mixture was heated to 70° C. for 5 h. Aftercooling to room temperature, the reaction mixture was partitionedbetween DCM (25 mL) and water (25 mL). The aqueous layer was separatedand extracted with DCM (2×20 mL). The combined organic phases werewashed with saturated NaHCO₃ (3×25 mL) and brine (25 mL), dried oversodium sulfate and concentrated. The crude product was used directly inthe next step.

LCMS (ESI⁺): 330.2 (M+H)⁺

Step 2:(E)-3-(1′-Methyl-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-6-yl)acrylicacid hydrochloride

To a solution of (E)-ethyl3-(V-methyl-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-6-yl)acrylate(95 mg, 0.288 mmol) in DCM (2 mL) and EtOH (2 mL) was added 1N aqueoussodium hydroxide (1 mL, 1.000 mmol) and the reaction was stirred at rtovernight, after which TLC (DCM/MeOH, 9:1) showed full conversion. Next,the mixture was concentrated and the residue acidified with 1N HCl (5mL) and stirred for 1 h. The resulting white solids were isolated byfiltration, washed with H₂O and Et₂O and dried on the filter. Theproduct (47 mg, 48%) was obtained as an off-white solid.

LCMS (ESI⁺): m/z 302.2 (M+H)⁺

Step 3:(E)-1′-Methyl-6-(3-(3-(3-methylbenzofuran-2-yl)azetidin-1-yl)-3-oxoprop-1-enyl)-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one

To a solution of 3-(3-methylbenzofuran-2-yl)azetidine hydrochloride(21.7 mg, 0.097 mmol) and(E)-3-(V-methyl-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-6-yl)acrylicacid hydrochloride (22.0 mg, 0.065 mmol) in DMF (3 mL) were addedEDCI.HCl (18.9 mg, 0.099 mmol), HOAt (13.9 mg, 0.102 mmol) andN,N-diisopropylethylamine (57 μL, 0.333 mmol). The reaction was stirredat rt for 20 h., after which the mixture was partitioned between DCM andH₂O. The layers were separated and the aqueous layer extracted with DCM(3×). The combined organic layers were washed with brine (3×), driedover Na₂SO₄ and concentrated and the residue was purified by flashchromatography (DCM/MeOH, 5%->20%). The product (10.6 mg, 35%) wasobtained as a white powder.

LCMS (ESI⁺): m/z 471.3 (M+H)⁺

¹H-NMR (CDCl₃/CD₃OD, 400 MHz): δ (ppm): 8.79 (br s, 1H), 8.30 (s, 1H),7.80 (s, 1H), 7.64 (d, 15.6 Hz, 1H), 7.45 (dd, J=7.7, 12.4 Hz, 2H), 7.24(m, 2H, overlapping with solvent signal), 6.54 (d, J=15.4 Hz, 1H), 4.67(m, 2H), 4.47 (m, 2H), 4.12 (m, 1H), 2.97 (s, 2H), 2.80 (s, 3H), 2.31(m, 2H), 2.21 (s, 3H), 2.05 (m, 2H), 1.95-1.50 (m, 4H, overlapping withH₂O-signal).

Example 69(E)-6-(3-(3-(Benzofuran-2-yl)azetidin-1-yl)-3-oxoprop-1-en-1-yl)-1′-methyl-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one(E69)

To a solution of 3-(benzofuran-2-yl)azetidine hydrochloride (30 mg,0.086 mmol) and(E)-3-(1′-methyl-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-6-yl)acrylicacid hydrochloride (20 mg, 0.059 mmol) in dry DMF (4 mL) were addedEDCI.HCl (17.02 mg, 0.089 mmol), HOAt (12.09 mg, 0.089 mmol) and DIPEA(51 μL, 0.296 mmol). The reaction was stirred at room temperatureovernight. The mixture was partitioned between dichloromethane and H₂O,the layers were separated and the aqueous layer was extracted withdichloromethane (2×5 mL). The combined organic layers were washed withbrine (3×3 mL), dried over Na₂SO₄ and concentrated. The residue waschromatographic purified (silica gel, eluent dichloromethane/7M NH₃ inMeOH 98:2 to 95:5). The residue was further purified by preparative LCMS(Waters X-Bridge 50×19 mm 5 μm ODB in combination with Waters X-Bridgeguard 10×19 mm 5 μm, at 25 ml/min flow rate; detection of product bymass and UV signal; eluent 10 mM ammonia in milliQ water to 10 mMammonia in MeCN 5% to 95% gradient), to yield the title compound (2.6mg, 9.6%).

LCMS (ESI⁺): no target mass observed.

¹H NMR (CDCl₃, 400 MHz): δ (ppm): 8.30 (d, J=2.0 Hz, 1H), 7.83 (s, 1H),7.67-7.62 (m, 2H), 7.53 (d, J=7.6 Hz, 1H), 7.46 (d, J=7.6 Hz, 1H),7.31-7.21 (m, 2H, overlapping with CDCl3), 6.60 (s, 1H), 6.48 (d, J=15.4Hz, 1H), 4.68 (t, J=8.3 Hz, 1H), 4.53 (q, J=8.6 Hz, 2H), 4.40 (dd, J=6.0Hz and 10.3 Hz, 1H), 4.08 (m, 1H), 2.88 (s, 2H), 2.65-2.61 (m, 2H),2.43-2.39 (m, 2H), 2.32 (s, 3H), 2.07-2.01 (m, 2H), 1.55-1.48 (m, 2H,overlapping with H₂O).

Example 70 and 716-((E)-3-Oxo-3-(3-((E)-1-(propoxyimino)ethyl)azetidin-1-yl)prop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E70) and6-((E)-3-Oxo-3-(3-((Z)-1-(propoxyimino)ethyl)azetidin-1-yl)prop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one(E71)

An isomeric mixture (ratio 87:13) of6-((1E)-3-oxo-3-(3-(1-(propoxyimino)ethyl)azetidin-1-yl)prop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one(162 mg, 0.455 mmol) was separated by preparative LCMS (Waters X-Bridge50×19 mm 5 μm ODB in combination with Waters Xbridge guard 10×19 mm 5μm, at 25 ml/min flow rate; detection of product by mass and UV signal;eluent 10 mM ammonia in milliQ water to 10 mM ammonia in MeCN 5% to 95%gradient). The first eluting isomer (6.4 mg, 0.018 mmol) was identifiedas the Z-isomer (FAB311) and the second eluting isomer (89.0 mg, 0.25mmol) was identified as the E-isomer (FAB310). This identification wasbased on a weak NOE-interaction which was observed between themethyl-group (1.91 ppm) and the propyl-tail (4.01 ppm) for the E-isomer,which was absent in the NOESY-spectrum of the Z-isomer.

E-isomer (FAB310): LCMS (ESI⁺): 357.2 (M+H)⁺;

¹H-NMR (CDCl₃, 400 MHz): δ (ppm): 10.38 (s, 1H), 8.42 (s, 1H), 7.62 (m,2H), 6.45 (d, J=15.7 Hz, 1H), 4.44 (m, 2H), 4.30 (m, 1H), 4.15 (m, 1H),4.01 (t, J=6.7 Hz, 2H), 3.45 (m, 1H), 3.01 (t, J=7.6 Hz, 2H), 2.71 (t,J=7.6 Hz, 2H), 1.91 (s, 3H), 1.67 (m, 2H), 0.94 (t, J=7.4 Hz, 3H).

Z-isomer (FAB311): LCMS (ESI⁺): 357.2 (M+H)⁺;

¹H-NMR (CDCl₃, 400 MHz): δ (ppm): 9.53 (s, 1H), 8.39 (s, 1H), 7.63 (m,2H), 6.43 (d, J=15.6 Hz, 1H), 4.54 (m, 1H), 4.36-4.23 (m, 2H), 4.14 (m,1H), 3.98 (m, 3H), 3.01 (t, J=7.6 Hz, 2H), 2.71 (t, J=7.6 Hz, 2H), 2.02(s, 3H), 1.64 (m, 2H), 0.93 (t, J=7.5 Hz, 3H).

Assay Data 1. FabI Inhibition

The compounds of the invention are useful inhibitors of bacterial FabIenzyme.

Compound inhibitory activity of FabI enzyme is measured in vitro by theIC₅₀ determination using a fluorescence based assay.

The protein FabI from S. aureus is prepared and purified using standardmethods for recombinant protein expression after cloning of the gene ina prokaryotic expression vector.

The biochemical activity of the FabI enzyme is assessed using thefollowing method.

The assay buffer “AB” contained 50 mM ADA (N-(2-acetamido)iminodiaceticacid monosodium salt) pH 6.5, 1 mM dithiothreitol, 0.006% Triton-X100and 50 mM NaCl.

The following components are added in a white polystyrene Costar plate(Ref 3912) up to a final volume of 55.5 μL: 1.5 μL DMSO or inhibitordissolved in DMSO and 54 μL of a FabI/NADPH/NADP+ mixture in AB. After60 min of pre-incubation at room temperature, the reaction is started byaddition of 5 μL of trans-2-octenoyl N-acetylcysteamine thioester(t-o-NAC) to a final volume of 60.5 μL. This reaction mixture is thencomposed of 2 nM FabI, 40 μM NADPH (Sigma, N7505), 10 μM NADP+(Sigma,N5755), 100 μM t-O-NAC and compound at defined concentration.Fluorescence intensity of NADPH (λex=360 nm, λem=520 nm) is measuredimmediately after t-O-NAC addition (T0), and approximately 50 min later(T50) by a Fluostar Optima (BMG) so as to achieve ±30% of NADPHconversion. Enzyme activity is calculated by first subtracting T0 signalto T50 and then subtracting background signal (FabI=0). Percentages ofinhibition are calculated against untreated samples (Inhibitor=0) andIC₅₀ are fitted to a classical Langmuir equilibrium model using XLFIT(IDBS).

TABLE 1 In vitro inhibition of recombinant S. aureus FabI enzyme byselected compounds of formula (I) FabI Inhibition Example IC₅₀ (μM) 1 112 5.5 3 9.9 4 5.3 5 0.25 6 1.0 7 7.1 8 0.041 9 1.3 10 0.12 11 0.15 120.013 13 4.1 14 0.34 15 0.025 16 0.93 17 0.05 18 1.8 19 0.17 20 0.057 210.87 22 8.6 23 1.8 24 0.26 25 0.060 26 0.078 27 0.55 28 0.081

2. Antibacterial Activity

The compounds of the invention are useful antibacterial agents having aselective spectrum of activity in vitro against bacterial strainsrelying on FabI and related targets. Notably the compounds of theinvention show activity against Staphylococcus aureus includingmultiresistant strains. The activity is presented as Minimum InhibitoryConcentration (MIC) expressed in μg/ml and was determined using brothmicrodilution or Agar dilution methods.

Strains

Antibacterial activity was determined on strains from Mutabilis internalcollection. A description of the strains used in this study is providedin Table 2:

TABLE 2 Description of Strains Used in Antibacterial Study Genus SpeciesStrain ID Phenotype Genotype Provider Staphylococcus aureus CIP 54.146MSSA CRBIP Staphylococcus aureus NRS22 MRSA GISA, EryR, ClinR, SxtR,GmR, LevR mecA+, USA600 NARSA Staphylococcus aureus NRS100 MRSA TetRmecA+ NARSA Staphylococcus aureus NRS119 MRSA LinR, GmR, SxtR, CipRmecA+, G2576T NARSA Staphylococcus aureus NRS120 MRSA LinR, GmR, SxtR,CipR mecA+, G2576T NARSA Staphylococcus aureus NRS121 MRSA LinR, CipRmecA+, G2576T NARSA Staphylococcus aureus NRS123 MRSA TetR mecA+, USA400NARSA Staphylococcus aureus NRS127 MRSA LinR, CipR, EryR mecA+ NARSAStaphylococcus aureus NRS128 MSSA PenR, EryR, ClinR mecA− NARSAStaphylococcus aureus NRS130 MSSA EryR mecA− NARSA Staphylococcus aureusNRS192 MRSA mecA+ NARSA Staphylococcus aureus NRS262 MSSA PenR mecA−NARSA Staphylococcus aureus NRS269 MRSA TigR, EryR, CIinR, CipR, GenRmecA+ NARSA Staphylococcus aureus NRS382 MRSA EryR, ClinR, CipR mecA+,USA100 NARSA Staphylococcus aureus NRS383 MRSA EryR, ClinR, TetR, SxtR,LevR, GmR mecA+, USA200 NARSA Staphylococcus aureus NRS384 MRSA EryR,TetR mecA+, USA300 NARSA Staphylococcus aureus NRS385 MRSA EryR, ClinR,TetR, SxtR, LevR, GmR mecA+, USA500 NARSA Staphylococcus aureus NRS386MRSA EryR mecA+, USA700 NARSA Staphylococcus aureus NRS482 MRSA CipR,EryR, OxaR USA300 NARSA Staphylococcus aureus NRS483 MRSA mecA+, USA1000NARSA Staphylococcus aureus NRS484 MRSA mecA+, USA1100 NARSA (NARSA =Network on Antimicrobial Resistance in Staphylococcus aureus, CRBIP =Centre de Ressources Biologiques de l'Institut Pasteur)

MIC Determination Using Broth Microdilution Method

This protocol is compliant with Clinical Laboratory Standards Institute(CLSI) methodology as described in M7-A7 document of the CLSI. Thecompound to be tested is diluted according to a geometric series ofreason 2 in pure DMSO. Dilutions are transferred in sterile polystyrenemicroplates, followed by mid-log phase bacteria in cation-adjustedMuller-Hinton broth (ca-MHB, Fluka, Reference 90922) with a finalinoculum of 5×10⁵ cfu/ml. Microplates are incubated overnight at 35° C.MIC is defined as the lowest concentration of antimicrobial agent thatcompletely prevents visible bacterial growth. All manipulations, butcompound handling (in pure DMSO), are performed under sterileconditions. The final concentration of DMSO in the plates is 2%.

TABLE 3 Representative Examples of MIC (μg/ml) (Broth microdilution) byselected compounds of formula (I): S. aureus Example CIP 54.146 8 4 10 412 4 15 4

MIC Determination Using Agar Dilution Method

This protocol is compliant with Clinical Laboratory Standards Institute(CLSI) methodology as described in M7-A7 document of the CLSI. Thecompound to be tested is incorporated into Mueller-Hinton Agar medium(Fluka, Reference 70191) at one concentration per plate according to ageometric series of reason 2. Plates are inoculated with mid-log phasebacteria (inoculum=1×10⁴ cfu/spot) and incubated overnight at 35° C. MICis defined as the lowest concentration of antimicrobial agent thatcompletely inhibits bacterial growth. All manipulations, but compoundhandling (in pure DMSO), are performed under sterile conditions. Thefinal DMSO concentration of DMSO in the plates is 2%. Vancomycin is usedas reference.

TABLE 4 Representative examples of MIC (μg/ml) (Agar dilution) byselected compounds (Examples 12 and 15) of formula (I): StrainsVancomycin Example 12 Example 15 NRS22 4 4 4 NRS100 1 2 1 NRS119 1 2 2NRS120 1 2 2 NRS121 1 2 2 NRS123 1 2 2 NRS127 1 2 2 NRS128 1 1 1 NRS1301 2 2 NRS192 1 4 4 NRS262 1 4 4 NRS269 2 4 4 NRS382 1 4 4 NRS383 0.5 4 4NRS384 1 4 4 NRS385 1 2 4 NRS386 1 4 4 NRS482 1 4 4 NRS483 1 4 4 InNRS484 1 4 4

MIC Determination Using Susceptibility Method

Minimum inhibitory concentrations (MICs) were determined by brothmicrodilution according to CLSI guidelines (CLSI, M100-20¹, M7-A8²,M27-A3³). The compounds were tested in the range from 012-128 μg/ml.Colonies were taken directly from a second-pass culture plate andprepared to a suspension equivalent to the 0.5 McFarland standard usingnormal saline. Inoculation of the MIC plates took place within 15minutes after adjustment of the inoculum suspension turbidity. Thepanels were incubated at 35° C. for 16 to 20 hours before reading theMIC endpoints. The compounds of Examples 12, 29, 59, 63 and 66-71 weredissolved in DMSO to make the initial solutions of 5120 fag/ml. Thesesolutions were diluted 1:10 in sterile water to a stock solution of 512fag/ml. The stock solutions were further diluted into the appropriatebroth medium for the sequential dilutions used in the brothmicrodilution panels. S. pneumoniae was tested in Mueller Hinton (MH)broth with 3% lysed horse blood and C. albicans was tested in RPMI-1640medium. All other organisms were tested in MH broth.

TABLE 5 Representative Examples of MIC (μg/ml) (Broth microdilution) ofcompounds of Examples 12, 29, 59, 63 and 66-71; MSSA MRSA S. aureus E.coli E. faecalis S. pneumoniae C. albicans (IHMA (IHMA ATCC (ATCC (ATCC(ATCC (ATCC No #555189) #510059) 29213 25922) 29212) 49619) 90028) 12 11 1 >128 >128 >128 >128 29 0.5 0.5 0.5 >128 >128 >128 >128 59 0.06 0.060.06 64 64 32 128 63 1 1 1 64 64 64 128 66 0.25 0.5 0.25 64 64 64 64 670.06 0.06 0.06 >128 >128 128 >128 68 0.5 0.5 0.5 >128 >128 128 >128 69 11 1 >128 >128 128 >128 70 0.5 0.5 0.5 >128 >128 >128 >128 71 8 44 >128 >128 128 >128

The most active compounds were found to be Examples 59 and 67 whichexhibited MICs of 0.06 fag/ml against both MRSA and MSSA strains.

3. In Vivo Antibacterial Activity of Examples 12 and 15

An experimental model of infection by S. aureus was used to assess theantibacterial activity of FabI inhibitors.

Briefly in vivo studies were performed using groups of 5 week-oldneutropenic female Swiss mice (five mice per group for each condition).

The virulent methicillin susceptible Staphylococcus aureus strain ATCC29213 was grown to exponential phase in Tryptic soy (TS) broth culture.The bacterial culture is diluted to obtain a bacterial suspension of 1-310⁵ cfu/ml, washed in physiological serum and then inoculated to mice(1041 per mouse) by intra-muscle injection. The inoculums count wasverified by plating 10-fold dilutions of the suspension on TS agarplates immediately after inoculation.

The compound of Example 12 was dissolved and diluted in a formulationcontaining 80% Poly-Ethylen Glycol (PEG) 400 and an appropriate volumeof the solution (corresponding to a dose level of 100 mg/kg of bodyweight) was administered orally to each mouse, 1.5 h after the bacterialinfection. The negative control group received the 80% PEG400 solutionalone and Linezolid at 100 mg/kg was used as the positive control.

The compound of Example 15 was dissolved and diluted in a formulationcontaining 10% dimethyl sulfoxide (DMSO) and 20% hydroxy-propyl betacyclodextrine (HPCD) and an appropriate volume of the solution(corresponding to a dose level of 50 mg/kg of body weight) wasadministered subcutaneously to each mouse, 1.5 h after the bacterialinfection. The negative control group received the 10% DMSO and 20% HPCDsolution alone and Linezolid at 50 mg/kg was used as the positivecontrol.

Mice health and clinical signs were recorded during 20 h. At the end ofthis period mice were euthanized, thigh muscle recovered and homogenizedand bacterial count was determined by 10 fold dilution and platingmethod on TS agar plates.

All animal experiments were carried out in accordance with institutionalguidelines. Compound activity is measure by its effect at a given doseto reduce the bacterial burden in the thigh of infected mice.

As shown in FIG. 1 with the compound of Example 12 at 100 mg/kg and FIG.2 with the compound of Example 15 at 50 mg/kg, the compounds of theinvention, are able to protect mice against thigh dissemination.

4. HSA Binding Analysis of Examples 12, 29, 59, 63 and 67-71 Using aChiral HSA Column Test System

The test system used in this analysis was an HSA chiral column.

Reagents and Chemicals

Potassium phosphate monobasic KH₂PO₄ and potassium phosphate dibasictrihydrate K₂HPO₄, 3H₂O were obtained from Sigma-Aldrich. DMSO,2-propanol and sodium azide were purchased from Sigma-Aldrich. Water wasMilliQ grade obtained from Millipore system Milli-Q Plus (Waters).

Preparation of Reagents

20 mM K₂HPO₄: 3.484 g in 1 L of water20 mM KH₂PO₄: 2.722 g in 1 L of water20 mM Phosphate buffer pH 7.0: 58.7% of 20 mM K₂HPO₄+41.3% of 20 mMKH₂PO₄ (the pH is adjusted if necessary).

Preparation of Stock Solutions, Calibration and Quality Control Samples

Solutions of Examples 12, 29, 59, 63 and 67-71 were prepared inpotassium phosphate buffer, pH 7.0 to concentrations of 1 mM.

Equipment

HPLC system Alliance 2695 (Waters)PDA UV detector 996 (Waters)

Column Chiral HSA 50×3.0 mm, 5 μm (Chromtec)

AT261 scale (Mettler-Toledo)pH-meter easy seven (Mettler-Toledo)

Pipetman (Eppendorf) Vortex (Fisher-Bioblock)

Ultrasound bath4 mL glass vials (Dutscher)2 mL glass vials for chromatography (Waters)

Liquid Chromatography Parameters

Liquid Chromatography was used in accordance with the parameters shownin Table 6:

TABLE 6 Chromatographic parameters HPLC system Alliance 2695 (Waters)Column Chiral HSA 50 × 3.0 mm, 5 μm (Chromtec) Flow rate 0.5 mL/minColumn temperature 37° C. Auto sampler temperature Room TemperatureMobile Phase 94% 20 mM Potassium phosphate buffer pH 7.0 6% 2-propanolDetection For each unknown compound the optimal wavelength (λ_(max)) wasdetermined and subsequent detections were performed at the specificλ_(max) of the compound Injected volume 10 μL Monitoring and processingdata Empower2 (Waters) softwares

Percentage Binding Calculation

The relationship between the retention time (Tr) and percentage ofalbumin binding (AB %) depended on the dead time (T0) and the capacityfactor (k′):

AB%=[k′/(k′+1)]*100

-   -   where k′=(Tr−T0)/T0        HSA binding was classified as follows:        AB<75%: Low binding        75%≦AB<90%: Moderate binding        AB≧90%: High binding

Results

The results of the HSA binding analysis are shown in Table 7 wherein itcan be seen that five compounds had a low affinity (E12, E29, E63, E70and E71), three compounds had a moderate affinity (E59, E67 and E69) andone compound (E68) had a high affinity in vitro to human albumin.

TABLE 7 HSA binding data for Examples 12, 29, 59, 63 and 67−71 HSAExample T0 Tr Binding Number (min) (min) k′ (%) Conclusion E12 0.7721.410 0.826 45.2 Low binding E29 0.771 1.743 1.259 55.7 Low binding E590.771 4.378 4.678 82.4 Moderate binding E63 0.769 1.760 1.288 56.3 Lowbinding E67 0.772 7.229 8.360 89.3 Moderate binding E68 0.771 9.41411.216 91.8 High binding E69 0.771 6.734 7.730 88.5 Moderate binding E700.771 1.219 0.580 36.7 Low binding E71 0.772 1.084 0.404 28.8 Lowbinding

CLSI Guideline References 1. M100-S20

Clinical and Laboratory Standards Institute, 2010. Performance Standardsfor Antimicrobial Susceptibility Testing; Twentieth InformationalSupplement. CLSI document M100-520. Clinical and Laboratory StandardsInstitute (CLSI), Wayne, Pa. 19087-1898 USA.

2. M7-A8

Clinical and Laboratory Standards Institute (CLSI), 2009. Methods forDilution Antimicrobial Test for Bacteria That Grow Aerobically; ApprovedStandard—Eighth Edition. CLSI document M07-A8 [ISBN 1-56238-689-1].CLSI, 940 West Valley Road, Suite 1400, Wayne, Pa. 19087 USA.

3. M27-A3

Clinical and Laboratory Standards Institute, 2009. Reference method forbroth dilution antifungal broth susceptibility testing ofyeasts—Approved Standard Third Edition. CLSI document M27-A3. Clinicaland Laboratory Standards Institute (CLSI), Wayne, Pa. 19087-1898 USA.

The invention embraces all combinations of preferred and more preferredgroups and suitable and more suitable groups and embodiments of groupsrecited above.

Throughout the specification and the claims which follow, unless thecontext requires otherwise, the word ‘comprise’, and variations such as‘comprises’ and ‘comprising’, will be understood to imply the inclusionof a stated integer, step, group of integers or group of steps but notto the exclusion of any other integer, step, group of integers or groupof steps.

All patents and patent applications referred to herein are incorporatedby reference in their entirety.

The application of which this description and claims forms part may beused as a basis for priority in respect of any subsequent application.The claims of such subsequent application may be directed to any featureor combination of features described herein. They may take the form ofproduct, composition, process, or use claims and may include, by way ofexample and without limitation, the claims.

We claim:
 1. A compound of formula (I):

wherein: W and X independently represent a bond or a —(CH₂)₁₋₄ group,such that W and X together contain 1-5 carbon atoms; R1 represents an H,F, CN, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, CO₂R_(d),COR_(d), CONR_(a)R_(b), OCOR_(d), OR_(d), NR_(a)R_(b), ON═CR_(d)R_(e),NR_(c)COR_(d), NR_(c)COOR_(d), OCONR_(a)R_(b), NR_(c)CONR_(a)R_(b),NR_(c)SO₂R_(a), S(O)_(n)R_(a), SO₂NR_(a)R_(b), —C(R_(a))═N—O—R_(f), Y—Aror a Z-Het group, wherein Ar represents phenyl or naphthyl, Hetrepresents a 4-10 membered monocyclic or bicyclic saturated orunsaturated heterocycle containing 1-5 heteroatoms selected from N, Oand S and Y and Z independently represent a bond or a linker selectedfrom O, S, CO, (C₁-C₆) alkylene, —O—(C₁-C₆) alkylene, —CO—(C₁-C₆)alkylene or —ON═CR_(d)—(C₁-C₆) alkylene, wherein said R1 group may beoptionally substituted by one or more R4 groups; R2 represents an H, F,ON, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, CO₂R_(d), COR_(d),CONR_(a)R_(b), OCOR_(d), OR_(d), NR_(a)R_(b), ON═CR_(d)R_(e),NR_(c)COR_(d), NR_(c)COOR_(d), OCONR_(a)R_(b), NR_(c)CONR_(a)R_(b),NR_(c)SO₂R_(a), S(O)_(n)R_(a), or SO₂NR_(a)R_(b) group; R_(a), R_(b) andR_(c) independently represent H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆)alkynyl, or an NR_(a)R_(b) group may optionally form a 3- to 7-memberednitrogen containing saturated heterocycle optionally containing 1 to 3additional heteroatoms selected from N, O or S wherein said heterocyclemay be optionally substituted by one or more (C₁-C₆) alkyl groups; R_(d)and R_(e) independently represent H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, halo(C₁-C₆) alkyl, halo(C₁-C₆) alkyl-O—(C₁-C₆) alkyl-or (C₁-C₆) alkyl-O—(C₁-C₆) alkyl-; R_(f) represents (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, halo(C₁-C₆) alkyl or —(C₁-C₆)alkyl-Ar, wherein Ar represents phenyl or naphthyl; —R4 representshalogen, ON, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, CO₂R_(d),COR_(d), CONR_(a)R_(b), OCOR_(d), OR_(d), NR_(a)R_(b), ON═CR_(d)R_(e),NR_(c)COR_(d), NR_(c)COOR_(d), OCONR_(a)R_(b), NR_(c)CONR_(a)R_(b),NR_(c)SO₂R_(a), S(O)_(n)R_(a), or SO₂NR_(a)R_(b); n represents aninteger selected from 0 to 2; R3 represents a heterocycle of formula(d):

wherein said R3 group may be optionally substituted by one or more R5groups; R5 is selected from the group consisting of F, CO₂R_(d),COR_(d), CONR_(a)R_(b), OR_(d), ═O, NR_(a)R_(b), NR_(c)COR_(d) or(C₁-C₆) alkyl optionally substituted by F, CO₂R_(d), CONR_(a)R_(b),OR_(d), NR_(a)R_(b), NR_(a)COR_(d) or Het optionally substituted by oneor more (C₁-C₆) alkyl groups, or two R5 groups together with the atom towhich they are attached may together form a Het group optionallysubstituted by one or more (C₁-C₆) alkyl groups; or a pharmaceuticallyacceptable salt or solvate thereof.
 2. A compound as defined in claim 1,wherein W and X both represent CH₂, one of W and X represents CH₂ andthe other represents CH₂CH₂, one of W and X represents a bond and theother represents CH₂CH₂CH₂, W and X both represent CH₂CH₂, one of W andX represents CH₂ and the other represents CH₂CH₂, or one of W and Xrepresents a bond and the other represents CH₂CH₂CH₂CH₂.
 3. A compoundas defined in claim 2, wherein W and X both represent CH₂.
 4. A compoundas defined in claim 1, wherein R1 represents an H, F, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, OR_(d), S(O)_(n)R_(a), —C(R_(a))═N—O—R_(f), Y—Ar orZ-Het group each of which may be optionally substituted by one or moreR4 groups.
 5. A compound as defined in claim 4, wherein R1 representsOR_(d), Z-Het or —C(R_(a))═N—O—R_(f).
 6. A compound as defined in claim1, wherein R2 represents an H or OR_(d) group.
 7. A compound as definedin claim 1, wherein R4 represents halogen, (C₁-C₆) alkyl, (C₂-C₆)alkenyl or (C₂-C₆)alkynyl.
 8. A compound as defined in claim 1, whereinR3 is substituted by one or more R5 groups: CO₂R_(d), NR_(a)R_(b),CONR_(a)R_(b), NR_(c)COR_(d) or (C₁-C₆) alkyl optionally substituted byF, CO₂R_(d), CONR_(a)R_(b), OR_(d), NR_(a)R_(b), NR_(a)COR_(d) or Hetoptionally substituted by one or more (C₁-C₆) alkyl groups.
 9. Acompound of formula (I) as defined in claim 1 which is:(E)-7-(3-Oxo-3-(3-(thiophen-2-ylmethoxy)azetidin-1-yl)prop-1-enyl)-4,5-dihydro-1H-pyrido[2,3-e][1,4]diazepin-2(3H)-one(E42); or a pharmaceutically acceptable salt or solvate thereof.
 10. Aprocess for preparing the compound of formula (I) as defined in claim 1,which comprises: (a) reacting a compound of formula (II):

wherein R3 is as defined above for compounds of formula (I), with acompound of formula (III):

wherein W, X, R1 and R2 are as defined above for compounds of formula(I); or (b) reacting a compound of formula (IV):

wherein R3 is as defined above for compounds of formula (I) and L¹represents a suitable leaving group, such as a halogen atom, e.g.fluorine, chlorine, bromine or an alkoxy group, with a compound offormula (III):

wherein W, X, R1 and R2 are as defined above for compounds of formula(I); or (c) reacting a compound of formula (V):

wherein W, X, R1 and R2 are as defined above for compounds of formula(I), with a compound of formula L²-R3, wherein L² represents a suitableleaving group, such as a halogen atom, e.g. fluorine, chlorine, bromineor an alkoxy group; optionally thereafter followed by: (d) deprotectinga protected derivative of compound (I); and optionally thereafterfollowed by: (e) interconversion of a compound of formula (I) to afurther compound of formula (I).